TY - JOUR T1 - Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group. JF - Stroke Y1 - 1991 A1 - O'Leary, D H A1 - Polak, J F A1 - Wolfson, S K A1 - Bond, M G A1 - Bommer, W A1 - Sheth, S A1 - Psaty, B M A1 - Sharrett, A R A1 - Manolio, T A KW - Age Factors KW - Aged KW - Arteriosclerosis KW - Carotid Arteries KW - Carotid Artery Diseases KW - Carotid Artery, Internal KW - Female KW - Humans KW - Image Interpretation, Computer-Assisted KW - Image Processing, Computer-Assisted KW - Male KW - Prospective Studies KW - Ultrasonography AB -

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.

VL - 22 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1926258?dopt=Abstract ER - TY - JOUR T1 - Assessing the use of medications in the elderly: methods and initial experience in the Cardiovascular Health Study. The Cardiovascular Health Study Collaborative Research Group. JF - J Clin Epidemiol Y1 - 1992 A1 - Psaty, B M A1 - Lee, M A1 - Savage, P J A1 - Rutan, G H A1 - German, P S A1 - Lyles, M KW - Aged KW - Aged, 80 and over KW - Cerebrovascular Disorders KW - Coronary Disease KW - Data Collection KW - Drug Utilization KW - Female KW - Humans KW - Male KW - Prospective Studies KW - Risk Factors KW - United States AB -

The 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.

VL - 45 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1607909?dopt=Abstract ER - TY - JOUR T1 - Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. JF - Stroke Y1 - 1992 A1 - O'Leary, D H A1 - Polak, J F A1 - Kronmal, R A A1 - Kittner, S J A1 - Bond, M G A1 - Wolfson, S K A1 - Bommer, W A1 - Price, T R A1 - Gardin, J M A1 - Savage, P J KW - Aged KW - Arteriosclerosis KW - Cardiomegaly KW - Carotid Artery Diseases KW - Cerebrovascular Disorders KW - Coronary Disease KW - Female KW - Humans KW - Male KW - Medical Records KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Ultrasonography AB -

BACKGROUND 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.

VL - 23 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1448826?dopt=Abstract ER - TY - JOUR T1 - The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1992 A1 - Tracy, R P A1 - Bovill, E G A1 - Fried, L P A1 - Heiss, G A1 - Lee, M H A1 - Polak, J F A1 - Psaty, B M A1 - Savage, P J KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Female KW - Fibrinogen KW - Humans KW - Male KW - Middle Aged KW - Risk Factors AB -

The 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.

VL - 2 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1342301?dopt=Abstract ER - TY - JOUR T1 - Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study. JF - JAMA Y1 - 1992 A1 - Psaty, B M A1 - Furberg, C D A1 - Kuller, L H A1 - Borhani, N O A1 - Rautaharju, P M A1 - O'Leary, D H A1 - Bild, D E A1 - Robbins, J A1 - Fried, L P A1 - Reid, C KW - Aged KW - Aged, 80 and over KW - Cardiomegaly KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - Cerebrovascular Disorders KW - Coronary Disease KW - Cross-Sectional Studies KW - Echocardiography KW - Electrocardiography KW - Female KW - Humans KW - Hypertension KW - Male KW - Myocardial Infarction KW - Prospective Studies KW - Risk Factors KW - Systole AB -

OBJECTIVE: 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.

VL - 268 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1387172?dopt=Abstract ER - TY - JOUR T1 - Major electrocardiographic abnormalities in persons aged 65 years and older (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group. JF - Am J Cardiol Y1 - 1992 A1 - Furberg, C D A1 - Manolio, T A A1 - Psaty, B M A1 - Bild, D E A1 - Borhani, N O A1 - Newman, A A1 - Tabatznik, B A1 - Rautaharju, P M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Arrhythmias, Cardiac KW - Chi-Square Distribution KW - Electrocardiography KW - Female KW - Heart Diseases KW - Humans KW - Logistic Models KW - Male KW - Prevalence KW - Risk Factors KW - Sex Factors KW - United States AB -

Electrocardiographic 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.

VL - 69 IS - 16 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1585868?dopt=Abstract ER - TY - JOUR T1 - Age-related trends in cardiovascular morbidity and physical functioning in the elderly: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 1993 A1 - Bild, D E A1 - Fitzpatrick, A A1 - Fried, L P A1 - Wong, N D A1 - Haan, M N A1 - Lyles, M A1 - Bovill, E A1 - Polak, J F A1 - Schulz, R KW - Activities of Daily Living KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Prevalence KW - Sex Distribution KW - Socioeconomic Factors AB -

OBJECTIVE: 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.

VL - 41 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8409149?dopt=Abstract ER - TY - JOUR T1 - Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group. JF - Circulation Y1 - 1993 A1 - Newman, A B A1 - Siscovick, D S A1 - Manolio, T A A1 - Polak, J A1 - Fried, L P A1 - Borhani, N O A1 - Wolfson, S K KW - Aged KW - Ankle KW - Arm KW - Arteriosclerosis KW - Blood Pressure Determination KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Multivariate Analysis KW - Peripheral Vascular Diseases KW - Population Surveillance KW - Predictive Value of Tests KW - Risk Factors AB -

BACKGROUND: 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.

VL - 88 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8353913?dopt=Abstract ER - TY - JOUR T1 - Assessment of cerebrovascular disease in the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1993 A1 - Price, T R A1 - Psaty, B A1 - O'Leary, D A1 - Burke, G A1 - Gardin, J KW - Aged KW - Aged, 80 and over KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Longitudinal Studies KW - Male KW - Prevalence AB -

The 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.

VL - 3 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8167827?dopt=Abstract ER - TY - JOUR T1 - Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. The CHS Collaborative Research Group. JF - Circulation Y1 - 1993 A1 - Manolio, T A A1 - Furberg, C D A1 - Shemanski, L A1 - Psaty, B M A1 - O'Leary, D H A1 - Tracy, R P A1 - Bush, T L KW - Aged KW - Aging KW - Cardiovascular Diseases KW - Carotid Arteries KW - Carotid Stenosis KW - Electrocardiography KW - Estrogen Replacement Therapy KW - Female KW - Heart KW - Heart Ventricles KW - Humans KW - Patient Compliance KW - Risk Factors KW - Smoking KW - Ultrasonography AB -

BACKGROUND: 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.

VL - 88 IS - 5 Pt 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8222111?dopt=Abstract ER - TY - JOUR T1 - Prevalence of cardiovascular diseases among older adults. The Cardiovascular Health Study. JF - Am J Epidemiol Y1 - 1993 A1 - Mittelmark, M B A1 - Psaty, B M A1 - Rautaharju, P M A1 - Fried, L P A1 - Borhani, N O A1 - Tracy, R P A1 - Gardin, J M A1 - O'Leary, D H KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Bias KW - California KW - Cardiovascular Diseases KW - Electrocardiography KW - Female KW - Health Surveys KW - Humans KW - Longitudinal Studies KW - Male KW - Maryland KW - Mass Screening KW - North Carolina KW - Pennsylvania KW - Population Surveillance KW - Prevalence KW - Reproducibility of Results AB -

The 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.

VL - 137 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8452139?dopt=Abstract ER - TY - JOUR T1 - Sonographic evaluation of carotid artery atherosclerosis in the elderly: relationship of disease severity to stroke and transient ischemic attack. JF - Radiology Y1 - 1993 A1 - Polak, J F A1 - O'Leary, D H A1 - Kronmal, R A A1 - Wolfson, S K A1 - Bond, M G A1 - Tracy, R P A1 - Gardin, J M A1 - Kittner, S J A1 - Price, T R A1 - Savage, P J KW - Aged KW - Arteriosclerosis KW - Carotid Artery Diseases KW - Carotid Artery, Internal KW - Carotid Stenosis KW - Cerebrovascular Disorders KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Male KW - Ultrasonography AB -

Doppler 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.

VL - 188 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8327679?dopt=Abstract ER - TY - JOUR T1 - Temporal patterns of antihypertensive medication use among elderly patients. The Cardiovascular Health Study. JF - JAMA Y1 - 1993 A1 - Psaty, B M A1 - Savage, P J A1 - Tell, G S A1 - Polak, J F A1 - Hirsch, C H A1 - Gardin, J M A1 - McDonald, R H KW - Adrenergic beta-Antagonists KW - Aged KW - Analysis of Variance KW - Angiotensin-Converting Enzyme Inhibitors KW - Antihypertensive Agents KW - Calcium Channel Blockers KW - Cohort Studies KW - Diuretics KW - Drug Utilization KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Linear Models KW - Logistic Models KW - Male KW - Medicare KW - Practice Patterns, Physicians' KW - Recurrence KW - United States KW - Vasodilator Agents AB -

OBJECTIVES: 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.

VL - 270 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8105112?dopt=Abstract ER - TY - JOUR T1 - Correlates of blood pressure in community-dwelling older adults. The Cardiovascular Health Study. Cardiovascular Health Study (CHS) Collaborative Research Group. JF - Hypertension Y1 - 1994 A1 - Tell, G S A1 - Rutan, G H A1 - Kronmal, R A A1 - Bild, D E A1 - Polak, J F A1 - Wong, N D A1 - Borhani, N O KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cohort Studies KW - Coronary Disease KW - Female KW - Health Surveys KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Regression Analysis KW - United States AB -

Although 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)

VL - 23 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8282331?dopt=Abstract ER - TY - JOUR T1 - Correlates of QT prolongation in older adults (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group. JF - Am J Cardiol Y1 - 1994 A1 - Rautaharju, P M A1 - Manolio, T A A1 - Psaty, B M A1 - Borhani, N O A1 - Furberg, C D KW - Aged KW - Aged, 80 and over KW - Female KW - Humans KW - Logistic Models KW - Long QT Syndrome KW - Longitudinal Studies KW - Male KW - Sex Factors VL - 73 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8184870?dopt=Abstract ER - TY - JOUR T1 - Eating patterns of community-dwelling older adults: the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1994 A1 - Kumanyika, S A1 - Tell, G S A1 - Shemanski, L A1 - Polak, J A1 - Savage, P J KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cardiovascular Diseases KW - Cerebrovascular Disorders KW - Demography KW - Diet KW - Diet Surveys KW - Diet, Sodium-Restricted KW - Female KW - Humans KW - Male KW - Minority Groups KW - Prospective Studies KW - Risk Factors KW - Sex Factors AB -

We 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.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7981849?dopt=Abstract ER - TY - JOUR T1 - Magnetic resonance abnormalities and cardiovascular disease in older adults. The Cardiovascular Health Study. JF - Stroke Y1 - 1994 A1 - Manolio, T A A1 - Kronmal, R A A1 - Burke, G L A1 - Poirier, V A1 - O'Leary, D H A1 - Gardin, J M A1 - Fried, L P A1 - Steinberg, E P A1 - Bryan, R N KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Atrophy KW - Brain KW - Cerebral Ventricles KW - Cerebrovascular Disorders KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Regression Analysis KW - Risk Factors KW - Sex Factors AB -

BACKGROUND 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.

VL - 25 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8303738?dopt=Abstract ER - TY - JOUR T1 - A method for using MR to evaluate the effects of cardiovascular disease on the brain: the cardiovascular health study. JF - AJNR Am J Neuroradiol Y1 - 1994 A1 - Bryan, R N A1 - Manolio, T A A1 - Schertz, L D A1 - Jungreis, C A1 - Poirier, V C A1 - Elster, A D A1 - Kronmal, R A KW - Aged KW - Brain KW - Cerebral Infarction KW - Cerebral Ventricles KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Diagnosis, Differential KW - Feasibility Studies KW - Female KW - Humans KW - Image Interpretation, Computer-Assisted KW - Incidence KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Mass Screening KW - Observer Variation KW - Pilot Projects KW - Prospective Studies KW - Risk Factors KW - United States AB -

PURPOSE: 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.

VL - 15 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7847205?dopt=Abstract ER - TY - JOUR T1 - Predictors of perceived health status in elderly men and women. The Cardiovascular Health Study. JF - J Aging Health Y1 - 1994 A1 - Schulz, R A1 - Mittelmark, M A1 - Kronmal, R A1 - Polak, J F A1 - Hirsch, C H A1 - German, P A1 - Bookwala, J KW - Aged KW - Cardiovascular Diseases KW - Data Collection KW - Female KW - Forecasting KW - Geriatric Assessment KW - Health Status KW - Humans KW - Male KW - Multivariate Analysis KW - Regression Analysis KW - Self-Assessment KW - Sex Factors KW - United States AB -

Baseline 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.

VL - 6 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10138383?dopt=Abstract ER - TY - JOUR T1 - Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 1994 A1 - Furberg, C D A1 - Psaty, B M A1 - Manolio, T A A1 - Gardin, J M A1 - Smith, V E A1 - Rautaharju, P M KW - Aged KW - Aged, 80 and over KW - Anti-Arrhythmia Agents KW - Anticoagulants KW - Atrial Fibrillation KW - Blood Glucose KW - Cardiovascular Diseases KW - Chi-Square Distribution KW - Coronary Disease KW - Electrocardiography KW - Female KW - Humans KW - Male KW - Prevalence KW - Regression Analysis KW - Sampling Studies AB -

Atrial 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.

VL - 74 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8037127?dopt=Abstract ER - TY - JOUR T1 - Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study. JF - Am J Epidemiol Y1 - 1994 A1 - Kuller, L A1 - Borhani, N A1 - Furberg, C A1 - Gardin, J A1 - Manolio, T A1 - O'Leary, D A1 - Psaty, B A1 - Robbins, J KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Cardiovascular Diseases KW - Female KW - Humans KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Prevalence KW - Risk Factors KW - United States AB -

The 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.

VL - 139 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8209875?dopt=Abstract ER - TY - JOUR T1 - Relation of smoking with carotid artery wall thickness and stenosis in older adults. The Cardiovascular Health Study. The Cardiovascular Health Study (CHS) Collaborative Research Group. JF - Circulation Y1 - 1994 A1 - Tell, G S A1 - Polak, J F A1 - Ward, B J A1 - Kittner, S J A1 - Savage, P J A1 - Robbins, J KW - Aged KW - Aged, 80 and over KW - Carotid Arteries KW - Carotid Stenosis KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Smoking KW - Ultrasonography AB -

BACKGROUND: 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.

VL - 90 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7994837?dopt=Abstract ER - TY - JOUR T1 - Black-white differences in subclinical cardiovascular disease among older adults: the Cardiovascular Health Study. CHS Collaborative Research Group. JF - J Clin Epidemiol Y1 - 1995 A1 - Manolio, T A A1 - Burke, G L A1 - Psaty, B M A1 - Newman, A B A1 - Haan, M A1 - Powe, N A1 - Tracy, R P A1 - O'Leary, D H KW - African Continental Ancestry Group KW - Aged KW - Cardiovascular Diseases KW - Carotid Arteries KW - European Continental Ancestry Group KW - Female KW - Geriatric Assessment KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Sex Factors AB -

Cardiovascular 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.

VL - 48 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7636516?dopt=Abstract ER - TY - JOUR T1 - Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1995 A1 - Tracy, R P A1 - Bovill, E G A1 - Yanez, D A1 - Psaty, B M A1 - Fried, L P A1 - Heiss, G A1 - Lee, M A1 - Polak, J F A1 - Savage, P J KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Carotid Stenosis KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Humans KW - Multivariate Analysis KW - Prospective Studies KW - Regression Analysis KW - Risk Factors AB -

No 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.

VL - 15 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7670938?dopt=Abstract ER - TY - JOUR T1 - Hematological and biochemical laboratory values in older Cardiovascular Health Study participants. JF - J Am Geriatr Soc Y1 - 1995 A1 - Robbins, J A1 - Wahl, P A1 - Savage, P A1 - Enright, P A1 - Powe, N A1 - Lyles, M KW - Age Factors KW - Aged KW - Analysis of Variance KW - California KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Male KW - Maryland KW - Middle Aged KW - North Carolina KW - Pennsylvania KW - Reference Values KW - Risk Factors KW - Sex Characteristics AB -

OBJECTIVE: 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.

VL - 43 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7636091?dopt=Abstract ER - TY - JOUR T1 - Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1995 A1 - Psaty, B M A1 - Kuller, L H A1 - Bild, D A1 - Burke, G L A1 - Kittner, S J A1 - Mittelmark, M A1 - Price, T R A1 - Rautaharju, P M A1 - Robbins, J KW - Aged KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Electrocardiography KW - Epidemiologic Methods KW - False Negative Reactions KW - Female KW - Humans KW - Male KW - Population Surveillance KW - Prevalence KW - Prospective Studies KW - Reproducibility of Results KW - Risk Factors KW - Self Disclosure KW - United States AB -

The 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)

VL - 5 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8520708?dopt=Abstract ER - TY - JOUR T1 - Subclinical disease as an independent risk factor for cardiovascular disease. JF - Circulation Y1 - 1995 A1 - Kuller, L H A1 - Shemanski, L A1 - Psaty, B M A1 - Borhani, N O A1 - Gardin, J A1 - Haan, M N A1 - O'Leary, D H A1 - Savage, P J A1 - Tell, G S A1 - Tracy, R KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Odds Ratio KW - Reference Values KW - Risk Factors AB -

BACKGROUND: 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.

VL - 92 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7641349?dopt=Abstract ER - TY - JOUR T1 - Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1995 A1 - Ives, D G A1 - Fitzpatrick, A L A1 - Bild, D E A1 - Psaty, B M A1 - Kuller, L H A1 - Crowley, P M A1 - Cruise, R G A1 - Theroux, S KW - Aged KW - Cerebrovascular Disorders KW - Coronary Disease KW - Epidemiologic Methods KW - Female KW - Hospitalization KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Population Surveillance KW - Quality Control KW - United States AB -

While 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.

VL - 5 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8520709?dopt=Abstract ER - TY - JOUR T1 - Temporal patterns of antihypertensive medication use among older adults, 1989 through 1992. An effect of the major clinical trials on clinical practice? JF - JAMA Y1 - 1995 A1 - Psaty, B M A1 - Koepsell, T D A1 - Yanez, N D A1 - Smith, N L A1 - Manolio, T A A1 - Heckbert, S R A1 - Borhani, N O A1 - Gardin, J M A1 - Gottdiener, J S A1 - Rutan, G H KW - Aged KW - Antihypertensive Agents KW - Clinical Trials as Topic KW - Data Interpretation, Statistical KW - Drug Utilization Review KW - Female KW - Humans KW - Hypertension KW - Male KW - Practice Patterns, Physicians' KW - United States AB -

OBJECTIVE: 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.

VL - 273 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7723157?dopt=Abstract ER - TY - JOUR T1 - Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators. JF - Am J Epidemiol Y1 - 1996 A1 - Cushman, M A1 - Yanez, D A1 - Psaty, B M A1 - Fried, L P A1 - Heiss, G A1 - Lee, M A1 - Polak, J F A1 - Savage, P J A1 - Tracy, R P KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Cardiovascular Diseases KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Female KW - Fibrinogen KW - Humans KW - Linear Models KW - Logistic Models KW - Male KW - Prevalence KW - Risk Factors KW - Sex Distribution KW - United States AB -

The 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.

VL - 143 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8651228?dopt=Abstract ER - TY - JOUR T1 - Carotid artery measures are strongly associated with left ventricular mass in older adults (a report from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 1996 A1 - Kronmal, R A A1 - Smith, V E A1 - O'Leary, D H A1 - Polak, J F A1 - Gardin, J M A1 - Manolio, T A KW - Aged KW - Carotid Arteries KW - Cohort Studies KW - Female KW - Heart Ventricles KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Regression Analysis KW - Risk Factors KW - Ultrasonography AB -

Associations 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.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8610615?dopt=Abstract ER - TY - JOUR T1 - Compensatory increase in common carotid artery diameter. Relation to blood pressure and artery intima-media thickness in older adults. Cardiovascular Health Study. JF - Stroke Y1 - 1996 A1 - Polak, J F A1 - Kronmal, R A A1 - Tell, G S A1 - O'Leary, D H A1 - Savage, P J A1 - Gardin, J M A1 - Rutan, G H A1 - Borhani, N O KW - Aged KW - Blood Pressure KW - Carotid Artery, Common KW - Cross-Sectional Studies KW - Echocardiography KW - Female KW - Heart Ventricles KW - Humans KW - Hypertension KW - Male KW - Tunica Intima KW - Tunica Media AB -

BACKGROUND 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.

VL - 27 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8898807?dopt=Abstract ER - TY - JOUR T1 - Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. JF - Arterioscler Thromb Vasc Biol Y1 - 1996 A1 - Cushman, M A1 - Psaty, B M A1 - Macy, E A1 - Bovill, E G A1 - Cornell, E S A1 - Kuller, L H A1 - Tracy, R P KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Hemostasis KW - Humans KW - Male KW - Risk Factors KW - Thrombin AB -

Studies 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.

VL - 16 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8792770?dopt=Abstract ER - TY - JOUR T1 - Current estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHS Collaborative Research Group. Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1996 A1 - Jonas, H A A1 - Kronmal, R A A1 - Psaty, B M A1 - Manolio, T A A1 - Meilahn, E N A1 - Tell, G S A1 - Tracy, R P A1 - Robbins, J A A1 - Anton-Culver, H KW - Aged KW - Arteriosclerosis KW - Carotid Arteries KW - Carotid Stenosis KW - Cohort Studies KW - Confidence Intervals KW - Cross-Sectional Studies KW - Databases, Factual KW - Drug Therapy, Combination KW - Estrogen Replacement Therapy KW - Estrogens KW - Female KW - Health Status Indicators KW - Humans KW - Odds Ratio KW - Progestins KW - Reproductive History KW - Ultrasonography KW - United States KW - Women's Health AB -

The 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.

VL - 6 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8876842?dopt=Abstract ER - TY - JOUR T1 - Hypertension and outcomes research. From clinical trials to clinical epidemiology. JF - Am J Hypertens Y1 - 1996 A1 - Psaty, B M A1 - Siscovick, D S A1 - Weiss, N S A1 - Koepsell, T D A1 - Rosendaal, F R A1 - Lin, D A1 - Heckbert, S R A1 - Wagner, E H A1 - Furberg, C D KW - Clinical Trials as Topic KW - Epidemiologic Methods KW - Evidence-Based Medicine KW - Humans KW - Hypertension KW - Outcome Assessment (Health Care) AB -

Outcomes 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.

VL - 9 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8924268?dopt=Abstract ER - TY - JOUR T1 - Short-term predictors of incident stroke in older adults. The Cardiovascular Health Study. JF - Stroke Y1 - 1996 A1 - Manolio, T A A1 - Kronmal, R A A1 - Burke, G L A1 - O'Leary, D H A1 - Price, T R KW - Age Factors KW - Aged KW - Cardiovascular Physiological Phenomena KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors KW - Time Factors AB -

BACKGROUND 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.

VL - 27 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8784116?dopt=Abstract ER - TY - JOUR T1 - Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. JF - Stroke Y1 - 1996 A1 - O'Leary, D H A1 - Polak, J F A1 - Kronmal, R A A1 - Savage, P J A1 - Borhani, N O A1 - Kittner, S J A1 - Tracy, R A1 - Gardin, J M A1 - Price, T R A1 - Furberg, C D KW - Adult KW - Aged KW - Arteriosclerosis KW - Blood Pressure KW - Carotid Artery, Common KW - Carotid Artery, Internal KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus KW - Diabetic Angiopathies KW - Electrocardiography KW - Female KW - Humans KW - Male KW - Medical History Taking KW - Physical Examination KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Sex Characteristics KW - Smoking KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

BACKGROUND 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.

VL - 27 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8571414?dopt=Abstract ER - TY - JOUR T1 - The association of antihypertensive agents with MRI white matter findings and with Modified Mini-Mental State Examination in older adults. JF - J Am Geriatr Soc Y1 - 1997 A1 - Heckbert, S R A1 - Longstreth, W T A1 - Psaty, B M A1 - Murros, K E A1 - Smith, N L A1 - Newman, A B A1 - Williamson, J D A1 - Bernick, C A1 - Furberg, C D KW - Adrenergic beta-Antagonists KW - Aged KW - Aged, 80 and over KW - Antihypertensive Agents KW - Brain KW - Calcium Channel Blockers KW - Cognition KW - Cohort Studies KW - Cross-Sectional Studies KW - Diuretics KW - Female KW - Geriatric Assessment KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Risk Factors AB -

OBJECTIVES: 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.

VL - 45 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9400550?dopt=Abstract ER - TY - JOUR T1 - The association of antihypertensive medication with serum creatinine changes in older adults. JF - Am J Hypertens Y1 - 1997 A1 - Smith, N L A1 - Psaty, B M A1 - Heckbert, S R A1 - Lemaitre, R N A1 - Kates, D M A1 - Rutan, G H A1 - Bleyer, A KW - Aged KW - Antihypertensive Agents KW - Cohort Studies KW - Creatinine KW - Female KW - Humans KW - Male AB -

Many 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.

VL - 10 IS - 12 Pt 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9443772?dopt=Abstract ER - TY - JOUR T1 - Clinically serious abnormalities found incidentally at MR imaging of the brain: data from the Cardiovascular Health Study. JF - Radiology Y1 - 1997 A1 - Yue, N C A1 - Longstreth, W T A1 - Elster, A D A1 - Jungreis, C A A1 - O'Leary, D H A1 - Poirier, V C KW - Aged KW - Aged, 80 and over KW - Brain KW - Brain Diseases KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male AB -

PURPOSE: 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.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988190?dopt=Abstract ER - TY - JOUR T1 - Incidence of and risk factors for atrial fibrillation in older adults. JF - Circulation Y1 - 1997 A1 - Psaty, B M A1 - Manolio, T A A1 - Kuller, L H A1 - Kronmal, R A A1 - Cushman, M A1 - Fried, L P A1 - White, R A1 - Furberg, C D A1 - Rautaharju, P M KW - Adult KW - Aged KW - Atrial Fibrillation KW - Blood Glucose KW - Blood Pressure KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Hospital Records KW - Humans KW - Incidence KW - Male KW - Prospective Studies KW - Risk Factors KW - United States AB -

BACKGROUND: 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.

VL - 96 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9337224?dopt=Abstract ER - TY - JOUR T1 - Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly--data from the Cardiovascular Health Study. JF - Radiology Y1 - 1997 A1 - Bryan, R N A1 - Wells, S W A1 - Miller, T J A1 - Elster, A D A1 - Jungreis, C A A1 - Poirier, V C A1 - Lind, B K A1 - Manolio, T A KW - Aged KW - Brain KW - Cardiovascular Diseases KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Prevalence AB -

PURPOSE: 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.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988191?dopt=Abstract ER - TY - JOUR T1 - Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. JF - Arterioscler Thromb Vasc Biol Y1 - 1997 A1 - Tracy, R P A1 - Psaty, B M A1 - Macy, E A1 - Bovill, E G A1 - Cushman, M A1 - Cornell, E S A1 - Kuller, L H KW - Aged KW - Body Mass Index KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Multivariate Analysis KW - Risk Factors KW - Smoking AB -

Blood 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.

VL - 17 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9351386?dopt=Abstract ER - TY - JOUR T1 - Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. JF - Arterioscler Thromb Vasc Biol Y1 - 1997 A1 - Tracy, R P A1 - Lemaitre, R N A1 - Psaty, B M A1 - Ives, D G A1 - Evans, R W A1 - Cushman, M A1 - Meilahn, E N A1 - Kuller, L H KW - Aged KW - Aging KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Case-Control Studies KW - Female KW - Humans KW - Male KW - Prospective Studies KW - Sex Factors AB -

Markers 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.

VL - 17 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9194763?dopt=Abstract ER - TY - JOUR T1 - Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. JF - Stroke Y1 - 1997 A1 - Price, T R A1 - Manolio, T A A1 - Kronmal, R A A1 - Kittner, S J A1 - Yue, N C A1 - Robbins, J A1 - Anton-Culver, H A1 - O'Leary, D H KW - Aged KW - Aged, 80 and over KW - Cerebral Infarction KW - Cognition KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Neurologic Examination AB -

BACKGROUND 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.

VL - 28 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9183343?dopt=Abstract ER - TY - JOUR T1 - Sulcal, ventricular, and white matter changes at MR imaging in the aging brain: data from the cardiovascular health study. JF - Radiology Y1 - 1997 A1 - Yue, N C A1 - Arnold, A M A1 - Longstreth, W T A1 - Elster, A D A1 - Jungreis, C A A1 - O'Leary, D H A1 - Poirier, V C A1 - Bryan, R N KW - Aged KW - Aged, 80 and over KW - Aging KW - Brain KW - Cardiovascular Diseases KW - Cerebral Ventricles KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Reproducibility of Results KW - Sex Factors AB -

PURPOSE: 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.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988189?dopt=Abstract ER - TY - JOUR T1 - Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly. The Cardiovascular Health Study. JF - Stroke Y1 - 1998 A1 - Longstreth, W T A1 - Shemanski, L A1 - Lefkowitz, D A1 - O'Leary, D H A1 - Polak, J F A1 - Wolfson, S K KW - Aged KW - Blood Flow Velocity KW - Carotid Artery, Internal KW - Carotid Stenosis KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - Systole KW - Ultrasonography, Doppler AB -

BACKGROUND 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.

VL - 29 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9804651?dopt=Abstract ER - TY - JOUR T1 - A brain image database for structure/function analysis. JF - AJNR Am J Neuroradiol Y1 - 1998 A1 - Letovsky, S I A1 - Whitehead, S H A1 - Paik, C H A1 - Miller, G A A1 - Gerber, J A1 - Herskovits, E H A1 - Fulton, T K A1 - Bryan, R N KW - Brain KW - Brain Mapping KW - Cerebral Infarction KW - Databases as Topic KW - Humans KW - Image Processing, Computer-Assisted KW - Magnetic Resonance Imaging KW - Neurologic Examination AB -

BACKGROUND 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.

VL - 19 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9874539?dopt=Abstract ER - TY - JOUR T1 - Correlates and prevalence of benzodiazepine use in community-dwelling elderly. JF - J Gen Intern Med Y1 - 1998 A1 - Gleason, P P A1 - Schulz, R A1 - Smith, N L A1 - Newsom, J T A1 - Kroboth, P D A1 - Kroboth, F J A1 - Psaty, B M KW - Aged KW - Aged, 80 and over KW - Benzodiazepines KW - Cross-Sectional Studies KW - Drug Utilization KW - Female KW - Humans KW - Male KW - Practice Patterns, Physicians' KW - Socioeconomic Factors AB -

OBJECTIVE: 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.

VL - 13 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9565387?dopt=Abstract ER - TY - JOUR T1 - Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. JF - Thromb Haemost Y1 - 1998 A1 - Sakkinen, P A A1 - Cushman, M A1 - Psaty, B M A1 - Kuller, L H A1 - Bajaj, S P A1 - Sabharwal, A K A1 - Boineau, R A1 - Macy, E A1 - Tracy, R P KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Anticoagulants KW - Antithrombin III KW - Biomarkers KW - Cross-Sectional Studies KW - Disease Susceptibility KW - Female KW - Humans KW - Lipoproteins KW - Male KW - Prevalence KW - Protein C KW - Protein S KW - Reference Values KW - Risk Factors KW - Thrombosis AB -

The 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.

VL - 80 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9684799?dopt=Abstract ER - TY - JOUR T1 - Diabetes in older adults: comparison of 1997 American Diabetes Association classification of diabetes mellitus with 1985 WHO classification. JF - Lancet Y1 - 1998 A1 - Wahl, P W A1 - Savage, P J A1 - Psaty, B M A1 - Orchard, T J A1 - Robbins, J A A1 - Tracy, R P KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Glucose Tolerance Test KW - Humans KW - Male KW - Prevalence KW - Societies, Medical KW - World Health Organization AB -

BACKGROUND: 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.

VL - 352 IS - 9133 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9759743?dopt=Abstract ER - TY - JOUR T1 - Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. JF - Thromb Haemost Y1 - 1998 A1 - Cushman, M A1 - Rosendaal, F R A1 - Psaty, B M A1 - Cook, E F A1 - Valliere, J A1 - Kuller, L H A1 - Tracy, R P KW - Adult KW - Age Factors KW - Aged KW - Arteries KW - Factor V KW - Female KW - Humans KW - Male KW - Middle Aged KW - Mutation KW - Risk Factors KW - Thrombosis AB -

Coagulation 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.

VL - 79 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9609219?dopt=Abstract ER - TY - JOUR T1 - Factors Associated With Hospital Utilization in the Elderly: From the Cardiovascular Health Study. JF - Am J Geriatr Cardiol Y1 - 1998 A1 - Robbins, J. A. A1 - Yanez, D. A1 - Powe, N. R. A1 - Savage, P. J. A1 - Ives, D. G. A1 - Gardin, J. M. A1 - Lyles, M. AB -

OBJECTIVE: 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.

VL - 7 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11416456?dopt=Abstract ER - TY - JOUR T1 - Hypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. JF - Radiology Y1 - 1998 A1 - Polak, J F A1 - Shemanski, L A1 - O'Leary, D H A1 - Lefkowitz, D A1 - Price, T R A1 - Savage, P J A1 - Brant, W E A1 - Reid, C KW - Aged KW - Aged, 80 and over KW - Carotid Artery, Internal KW - Carotid Stenosis KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Humans KW - Intracranial Arteriosclerosis KW - Male KW - Proportional Hazards Models KW - Risk KW - Ultrasonography, Doppler, Duplex KW - Ultrasonography, Doppler, Transcranial AB -

PURPOSE: 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%.

VL - 208 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9722841?dopt=Abstract ER - TY - JOUR T1 - Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. JF - Arch Neurol Y1 - 1998 A1 - Longstreth, W T A1 - Bernick, C A1 - Manolio, T A A1 - Bryan, N A1 - Jungreis, C A A1 - Price, T R KW - Aged KW - Cerebral Infarction KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Multivariate Analysis KW - Risk Factors AB -

OBJECTIVE: 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.

VL - 55 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9740116?dopt=Abstract ER - TY - JOUR T1 - Predicting future years of healthy life for older adults. JF - J Clin Epidemiol Y1 - 1998 A1 - Diehr, P A1 - Patrick, D L A1 - Bild, D E A1 - Burke, G L A1 - Williamson, J D KW - Aged KW - Aged, 80 and over KW - Cost-Benefit Analysis KW - Female KW - Forecasting KW - Health Promotion KW - Health Status KW - Humans KW - Life Expectancy KW - Life Tables KW - Male KW - Probability KW - Quality-Adjusted Life Years KW - Sex Factors AB -

Cost-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.

VL - 51 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9539891?dopt=Abstract ER - TY - JOUR T1 - Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JF - JAMA Y1 - 1998 A1 - Fried, L P A1 - Kronmal, R A A1 - Newman, A B A1 - Bild, D E A1 - Mittelmark, M B A1 - Polak, J F A1 - Robbins, J A A1 - Gardin, J M KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Humans KW - Male KW - Mortality KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States AB -

CONTEXT: 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.

VL - 279 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9486752?dopt=Abstract ER - TY - JOUR T1 - Temporal patterns in the medical treatment of congestive heart failure with angiotensin-converting enzyme inhibitors in older adults, 1989 through 1995. JF - Arch Intern Med Y1 - 1998 A1 - Smith, N L A1 - Psaty, B M A1 - Pitt, B A1 - Garg, R A1 - Gottdiener, J S A1 - Heckbert, S R KW - Aged KW - Angiotensin-Converting Enzyme Inhibitors KW - Drug Utilization KW - Female KW - Heart Failure KW - Humans KW - Logistic Models KW - Male KW - Stroke Volume KW - Treatment Outcome KW - United States AB -

BACKGROUND: 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.

VL - 158 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9605778?dopt=Abstract ER - TY - JOUR T1 - Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 1998 A1 - Lemaitre, R N A1 - Furberg, C D A1 - Newman, A B A1 - Hulley, S B A1 - Gordon, D J A1 - Gottdiener, J S A1 - McDonald, R H A1 - Psaty, B M KW - Aged KW - Anticholesteremic Agents KW - Cholesterol, LDL KW - Cohort Studies KW - Female KW - Humans KW - Hypercholesterolemia KW - Male KW - Prevalence KW - Risk Factors KW - United States AB -

OBJECTIVES: 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.

VL - 158 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9738605?dopt=Abstract ER - TY - JOUR T1 - Utilities for major stroke: results from a survey of preferences among persons at increased risk for stroke. JF - Am Heart J Y1 - 1998 A1 - Samsa, G P A1 - Matchar, D B A1 - Goldstein, L A1 - Bonito, A A1 - Duncan, P W A1 - Lipscomb, J A1 - Enarson, C A1 - Witter, D A1 - Venus, P A1 - Paul, J E A1 - Weinberger, M KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Attitude to Health KW - Female KW - Health Status KW - Humans KW - Intracranial Embolism and Thrombosis KW - Male KW - Middle Aged KW - Quality of Life KW - Sex Distribution KW - Surveys and Questionnaires KW - United States AB -

BACKGROUND: 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.

VL - 136 IS - 4 Pt 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9778075?dopt=Abstract ER - TY - JOUR T1 - Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Newman, A B A1 - Shemanski, L A1 - Manolio, T A A1 - Cushman, M A1 - Mittelmark, M A1 - Polak, J F A1 - Powe, N R A1 - Siscovick, D KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Ankle KW - Arm KW - Blood Pressure Determination KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Predictive Value of Tests KW - Risk Factors KW - Sex Distribution KW - Survival Analysis AB -

Peripheral 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.

VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073955?dopt=Abstract ER - TY - JOUR T1 - Antidiabetic treatment trends in a cohort of elderly people with diabetes. The cardiovascular health study, 1989-1997. JF - Diabetes Care Y1 - 1999 A1 - Smith, N L A1 - Heckbert, S R A1 - Bittner, V A A1 - Savage, P J A1 - Barzilay, J I A1 - Dobs, A S A1 - Psaty, B M KW - Aged KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Drug Therapy KW - Female KW - Follow-Up Studies KW - Humans KW - Hypoglycemic Agents KW - Insulin KW - Male KW - Prospective Studies KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: 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.

VL - 22 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10332674?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. JF - Lancet Y1 - 1999 A1 - Barzilay, J I A1 - Spiekerman, C F A1 - Wahl, P W A1 - Kuller, L H A1 - Cushman, M A1 - Furberg, C D A1 - Dobs, A A1 - Polak, J F A1 - Savage, P J KW - Age Factors KW - Aged KW - Blood Glucose KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Diabetes Complications KW - Diabetes Mellitus KW - Fasting KW - Female KW - Glucose Intolerance KW - Humans KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Risk Factors KW - Sensitivity and Specificity KW - Societies, Medical KW - United States KW - World Health Organization AB -

BACKGROUND: 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.

VL - 354 IS - 9179 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10466662?dopt=Abstract ER - TY - JOUR T1 - Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. JF - N Engl J Med Y1 - 1999 A1 - O'Leary, D H A1 - Polak, J F A1 - Kronmal, R A A1 - Manolio, T A A1 - Burke, G L A1 - Wolfson, S K KW - Aged KW - Carotid Arteries KW - Cerebrovascular Disorders KW - Disease-Free Survival KW - Female KW - Humans KW - Incidence KW - Male KW - Myocardial Infarction KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

BACKGROUND: 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.

VL - 340 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9878640?dopt=Abstract ER - TY - JOUR T1 - Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Cushman, M A1 - Lemaitre, R N A1 - Kuller, L H A1 - Psaty, B M A1 - Macy, E M A1 - Sharrett, A R A1 - Tracy, R P KW - Age Factors KW - Aged KW - Angina Pectoris KW - Biomarkers KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinolysin KW - Fibrinolysis KW - Follow-Up Studies KW - Heart Arrest KW - Humans KW - Male KW - Myocardial Infarction KW - Plasminogen Activator Inhibitor 1 KW - Risk Factors AB -

Coagulation 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.

VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073948?dopt=Abstract ER - TY - JOUR T1 - Hormone replacement therapy, inflammation, and hemostasis in elderly women. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Cushman, M A1 - Meilahn, E N A1 - Psaty, B M A1 - Kuller, L H A1 - Dobs, A S A1 - Tracy, R P KW - Aged KW - Biomarkers KW - Case-Control Studies KW - Cross-Sectional Studies KW - Estrogens KW - Female KW - Hemostasis KW - Hormone Replacement Therapy KW - Humans KW - Inflammation KW - Progestins KW - Random Allocation KW - United Kingdom KW - United States AB -

Lipid-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.

VL - 19 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10195915?dopt=Abstract ER - TY - JOUR T1 - Prevalence and associations of MRI-demonstrated brain infarcts in elderly subjects with a history of transient ischemic attack. The Cardiovascular Health Study. JF - Stroke Y1 - 1999 A1 - Bhadelia, R A A1 - Anderson, M A1 - Polak, J F A1 - Manolio, T A A1 - Beauchamp, N A1 - Knepper, L A1 - O'Leary, D H KW - Aged KW - Brain KW - Cardiovascular Diseases KW - Cerebral Infarction KW - Cross-Sectional Studies KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Magnetic Resonance Imaging KW - Male KW - Odds Ratio KW - Population Surveillance KW - Predictive Value of Tests KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - United States AB -

BACKGROUND 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.

VL - 30 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9933275?dopt=Abstract ER - TY - JOUR T1 - Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Sakkinen, P A A1 - Cushman, M A1 - Psaty, B M A1 - Rodriguez, B A1 - Boineau, R A1 - Kuller, L H A1 - Tracy, R P KW - Aged KW - Aged, 80 and over KW - alpha-2-Antiplasmin KW - Antifibrinolytic Agents KW - Asian Continental Ancestry Group KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Fibrinolysin KW - Fibrinolysis KW - Humans KW - Insulin Resistance KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Plasminogen Activator Inhibitor 1 KW - Risk Factors AB -

Plasmin-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, VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073949?dopt=Abstract ER - TY - JOUR T1 - The reliability of medication inventory methods compared to serum levels of cardiovascular drugs in the elderly. JF - J Clin Epidemiol Y1 - 1999 A1 - Smith, N L A1 - Psaty, B M A1 - Heckbert, S R A1 - Tracy, R P A1 - Cornell, E S KW - Aged KW - Aspirin KW - Cardiovascular Agents KW - Digoxin KW - Humans KW - Hydrochlorothiazide KW - Patient Compliance KW - Propranolol KW - Reproducibility of Results AB -

Medication 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.

VL - 52 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10201655?dopt=Abstract ER - TY - JOUR T1 - Survival versus years of healthy life: which is more powerful as a study outcome? JF - Control Clin Trials Y1 - 1999 A1 - Diehr, P A1 - Patrick, D L A1 - Burke, G L A1 - Williamson, J KW - Aged KW - Angina Pectoris KW - Female KW - Follow-Up Studies KW - Health Status KW - Humans KW - Life Expectancy KW - Male KW - Quality-Adjusted Life Years KW - Randomized Controlled Trials as Topic KW - Research Design KW - Sample Size KW - Survival Analysis KW - Time Factors KW - Treatment Outcome AB -

Studies 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.

VL - 20 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10357499?dopt=Abstract ER - TY - JOUR T1 - Temporal trends in the use of anticoagulants among older adults with atrial fibrillation. JF - Arch Intern Med Y1 - 1999 A1 - Smith, N L A1 - Psaty, B M A1 - Furberg, C D A1 - White, R A1 - Lima, J A A1 - Newman, A B A1 - Manolio, T A KW - Aged KW - Anticoagulants KW - Aspirin KW - Atrial Fibrillation KW - Cerebrovascular Disorders KW - Drug Therapy KW - Electrocardiography KW - Female KW - Humans KW - Incidence KW - Male KW - Prevalence KW - Treatment Outcome KW - Warfarin AB -

BACKGROUND: 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.

VL - 159 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10421280?dopt=Abstract ER - TY - JOUR T1 - Traditional risk factors and subclinical disease measures as predictors of first myocardial infarction in older adults: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 1999 A1 - Psaty, B M A1 - Furberg, C D A1 - Kuller, L H A1 - Bild, D E A1 - Rautaharju, P M A1 - Polak, J F A1 - Bovill, E A1 - Gottdiener, J S KW - Age Distribution KW - Aged KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Risk KW - Risk Factors KW - Sex Distribution AB -

BACKGROUND: 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.

VL - 159 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10386510?dopt=Abstract ER - TY - JOUR T1 - Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JF - JAMA Y1 - 2000 A1 - Nieto, F J A1 - Young, T B A1 - Lind, B K A1 - Shahar, E A1 - Samet, J M A1 - Redline, S A1 - D'Agostino, R B A1 - Newman, A B A1 - Lebowitz, M D A1 - Pickering, T G KW - Adult KW - Aged KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Hypertension KW - Logistic Models KW - Male KW - Middle Aged KW - Obesity KW - Polysomnography KW - Sleep Apnea Syndromes KW - Snoring AB -

CONTEXT: 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.

VL - 283 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10770144?dopt=Abstract ER - TY - JOUR T1 - Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study. JF - Circulation Y1 - 2000 A1 - Siscovick, D S A1 - Schwartz, S M A1 - Corey, L A1 - Grayston, J T A1 - Ashley, R A1 - Wang, S P A1 - Psaty, B M A1 - Tracy, R P A1 - Kuller, L H A1 - Kronmal, R A KW - Adult KW - Age Factors KW - Aged KW - Antibodies, Bacterial KW - Antibodies, Viral KW - Case-Control Studies KW - Chlamydophila pneumoniae KW - Coronary Disease KW - Cytomegalovirus KW - Female KW - Herpesvirus 1, Human KW - HIV Antibodies KW - Humans KW - Immunoglobulin G KW - Male KW - Myocardial Infarction KW - Risk Factors AB -

BACKGROUND: 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 (

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.

VL - 102 IS - 19 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11067785?dopt=Abstract ER - TY - JOUR T1 - Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. JF - Diabetes Y1 - 2000 A1 - Pietropaolo, M A1 - Barinas-Mitchell, E A1 - Pietropaolo, S L A1 - Kuller, L H A1 - Trucco, M KW - Aged KW - Aged, 80 and over KW - Aging KW - Autoantibodies KW - Autoantigens KW - Autoimmunity KW - Blood Glucose KW - C-Reactive Protein KW - Diabetes Mellitus, Type 2 KW - Female KW - Fibrinogen KW - Glucose Tolerance Test KW - Glutamate Decarboxylase KW - Humans KW - Islets of Langerhans KW - Male KW - Membrane Proteins KW - Protein Tyrosine Phosphatases KW - Receptor-Like Protein Tyrosine Phosphatases, Class 8 AB -

In 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.

VL - 49 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10615947?dopt=Abstract ER - TY - JOUR T1 - Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. JF - J Am Coll Cardiol Y1 - 2000 A1 - Gottdiener, J S A1 - Arnold, A M A1 - Aurigemma, G P A1 - Polak, J F A1 - Tracy, R P A1 - Kitzman, D W A1 - Gardin, J M A1 - Rutledge, J E A1 - Boineau, R C KW - Aged KW - Aged, 80 and over KW - Coronary Disease KW - Female KW - Geriatric Assessment KW - Heart Failure KW - Humans KW - Ischemic Attack, Transient KW - Male KW - Prospective Studies KW - Risk Factors KW - Survival Rate AB -

OBJECTIVES: 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.

VL - 35 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10807470?dopt=Abstract ER - TY - JOUR T1 - Race- 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. JF - J Electrocardiol Y1 - 2000 A1 - Rautaharju, P M A1 - Park, L P A1 - Gottdiener, J S A1 - Siscovick, D A1 - Boineau, R A1 - Smith, V A1 - Powe, N R KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Anthropometry KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Predictive Value of Tests KW - Prevalence KW - Sex Factors KW - Ultrasonography AB -

The 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.

VL - 33 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10954373?dopt=Abstract ER - TY - JOUR T1 - Area characteristics and individual-level socioeconomic position indicators in three population-based epidemiologic studies. JF - Ann Epidemiol Y1 - 2001 A1 - Diez-Roux, A V A1 - Kiefe, C I A1 - Jacobs, D R A1 - Haan, M A1 - Jackson, S A A1 - Nieto, F J A1 - Paton, C C A1 - Schulz, R KW - Adult KW - Black or African American KW - Cardiovascular Diseases KW - Demography KW - Educational Status KW - Factor Analysis, Statistical KW - Humans KW - Income KW - Linear Models KW - Occupations KW - Risk Factors KW - Social Class KW - Social Environment KW - Socioeconomic Factors KW - Statistics, Nonparametric KW - United States KW - White People AB -

PURPOSE: 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.

VL - 11 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11454499?dopt=Abstract ER - TY - JOUR T1 - Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. JF - Arch Intern Med Y1 - 2001 A1 - Psaty, B M A1 - Furberg, C D A1 - Kuller, L H A1 - Cushman, M A1 - Savage, P J A1 - Levine, D A1 - O'Leary, D H A1 - Bryan, R N A1 - Anderson, M A1 - Lumley, T KW - Aged KW - Blood Pressure KW - Female KW - Humans KW - Male KW - Myocardial Infarction KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - Survival Rate KW - United States AB -

BACKGROUND: 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.

VL - 161 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11343441?dopt=Abstract ER - TY - JOUR T1 - Association between physical activity and markers of inflammation in a healthy elderly population. JF - Am J Epidemiol Y1 - 2001 A1 - Geffken, D F A1 - Cushman, M A1 - Burke, G L A1 - Polak, J F A1 - Sakkinen, P A A1 - Tracy, R P KW - Aged KW - Analysis of Variance KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Factor VIII KW - Female KW - Fibrinogen KW - Humans KW - Inflammation KW - Leukocyte Count KW - Male KW - Physical Exertion KW - Sex Factors KW - Smoking AB -

Higher 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.

VL - 153 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11157411?dopt=Abstract ER - TY - JOUR T1 - Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter. JF - J Cardiovasc Risk Y1 - 2001 A1 - Herrington, D M A1 - Fan, L A1 - Drum, M A1 - Riley, W A A1 - Pusser, B E A1 - Crouse, J R A1 - Burke, G L A1 - McBurnie, M A A1 - Morgan, T M A1 - Espeland, M A KW - Adolescent KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Circulation KW - Brachial Artery KW - Female KW - Humans KW - Male KW - Middle Aged KW - Observer Variation KW - Population Surveillance KW - Reproducibility of Results KW - Sex Factors KW - Vasodilation KW - Vasodilator Agents AB -

BACKGROUND: 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.

VL - 8 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11702039?dopt=Abstract ER - TY - JOUR T1 - Incidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study. JF - J Natl Med Assoc Y1 - 2001 A1 - Jackson, S A A1 - Burke, G L A1 - Thach, C A1 - Cushman, M A1 - Ives, D A1 - Powe, N A1 - Manolio, T A KW - Age Distribution KW - Aged KW - Black or African American KW - Coronary Disease KW - Female KW - Health Status KW - Humans KW - Incidence KW - Male KW - Predictive Value of Tests AB -

Although 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.

VL - 93 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11730114?dopt=Abstract ER - TY - JOUR T1 - Patterns of self-rated health in older adults before and after sentinel health events. JF - J Am Geriatr Soc Y1 - 2001 A1 - Diehr, P A1 - Williamson, J A1 - Patrick, D L A1 - Bild, D E A1 - Burke, G L KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Death KW - Female KW - Follow-Up Studies KW - Health Status KW - Health Status Indicators KW - Hip Fractures KW - Hospitalization KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Random Allocation KW - Time Factors AB -

OBJECTIVES: 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.

VL - 49 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11207840?dopt=Abstract ER - TY - JOUR T1 - Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women. JF - Br J Haematol Y1 - 2001 A1 - Cushman, M A1 - Psaty, B M A1 - Meilahn, E N A1 - Dobs, A S A1 - Kuller, L H KW - Aged KW - Antithrombins KW - Black People KW - Body Mass Index KW - Cross-Sectional Studies KW - Estrogen Replacement Therapy KW - Female KW - Humans KW - Logistic Models KW - Postmenopause KW - Progestins KW - Protein C KW - Risk Factors KW - Venous Thrombosis KW - White People AB -

The 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.

VL - 114 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11472362?dopt=Abstract ER - TY - JOUR T1 - Probabilities of transition among health states for older adults. JF - Qual Life Res Y1 - 2001 A1 - Diehr, P A1 - Patrick, D L KW - Age Factors KW - Aged KW - Aging KW - Female KW - Health Status KW - Humans KW - Male KW - Probability KW - Quality of Life KW - Regression Analysis KW - Sex Factors AB -

GOAL: 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.

VL - 10 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11763205?dopt=Abstract ER - TY - JOUR T1 - Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. JF - Am J Epidemiol Y1 - 2001 A1 - Newman, A B A1 - Nieto, F J A1 - Guidry, U A1 - Lind, B K A1 - Redline, S A1 - Pickering, T G A1 - Quan, S F KW - Adult KW - Aged KW - Analysis of Variance KW - Cardiovascular Diseases KW - Chi-Square Distribution KW - Cross-Sectional Studies KW - Female KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Risk Factors KW - Sleep Apnea Syndromes KW - United States AB -

Associations 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.

VL - 154 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11434366?dopt=Abstract ER - TY - JOUR T1 - Risk factors for hospitalized gastrointestinal bleeding among older persons. Cardiovascular Health Study Investigators. JF - J Am Geriatr Soc Y1 - 2001 A1 - Kaplan, R C A1 - Heckbert, S R A1 - Koepsell, T D A1 - Furberg, C D A1 - Polak, J F A1 - Schoen, R E A1 - Psaty, B M KW - Activities of Daily Living KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Anti-Inflammatory Agents, Non-Steroidal KW - Anticoagulants KW - Aspirin KW - Cardiovascular Diseases KW - Female KW - Gastrointestinal Hemorrhage KW - Hospitalization KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Smoking KW - United States AB -

OBJECTIVES: 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.

VL - 49 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11207865?dopt=Abstract ER - TY - JOUR T1 - The role of comorbidity in the assessment of intermittent claudication in older adults. JF - J Clin Epidemiol Y1 - 2001 A1 - Newman, A B A1 - Naydeck, B L A1 - Sutton-Tyrrell, K A1 - Polak, J F A1 - Kuller, L H KW - Aged KW - Angina Pectoris KW - Arterial Occlusive Diseases KW - Cerebrovascular Disorders KW - Cohort Studies KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Humans KW - Intermittent Claudication KW - Leg KW - Male KW - Prevalence KW - Sensitivity and Specificity KW - Surveys and Questionnaires AB -

The 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.

VL - 54 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11223327?dopt=Abstract ER - TY - JOUR T1 - Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. JF - Neurology Y1 - 2001 A1 - Bernick, C A1 - Kuller, L A1 - Dulberg, C A1 - Longstreth, W T A1 - Manolio, T A1 - Beauchamp, N A1 - Price, T KW - Aged KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Magnetic Resonance Imaging KW - Male KW - Predictive Value of Tests KW - Risk Factors KW - Stroke AB -

BACKGROUND: 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.

VL - 57 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11591840?dopt=Abstract ER - TY - JOUR T1 - Transforming self-rated health and the SF-36 scales to include death and improve interpretability. JF - Med Care Y1 - 2001 A1 - Diehr, P A1 - Patrick, D L A1 - Spertus, J A1 - Kiefe, C I A1 - McDonell, M A1 - Fihn, S D KW - Aged KW - Data Interpretation, Statistical KW - Death KW - Decision Making KW - Female KW - Health Status KW - Humans KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Models, Statistical KW - Quality of Life KW - ROC Curve KW - Surveys and Questionnaires AB -

BACKGROUND: 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.

VL - 39 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11458132?dopt=Abstract ER - TY - JOUR T1 - The aging and dying processes and the health of older adults. JF - J Clin Epidemiol Y1 - 2002 A1 - Diehr, Paula A1 - Williamson, Jeff A1 - Burke, Gregory L A1 - Psaty, Bruce M KW - Aged KW - Aging KW - Death KW - Female KW - Health Status Indicators KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Muscular Atrophy AB -

It 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.

VL - 55 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11864798?dopt=Abstract ER - TY - JOUR T1 - Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events. JF - Am J Hypertens Y1 - 2002 A1 - Hindorff, Lucia A A1 - Heckbert, Susan R A1 - Tracy, Russell A1 - Tang, Zhonghua A1 - Psaty, Bruce M A1 - Edwards, Karen L A1 - Siscovick, David S A1 - Kronmal, Richard A A1 - Nazar-Stewart, Valle KW - African Continental Ancestry Group KW - Aged KW - Blood Pressure KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Humans KW - Hypertension KW - Male KW - Polymorphism, Genetic KW - Receptor, Angiotensin, Type 1 KW - Receptors, Angiotensin KW - United States AB -

BACKGROUND: 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.

VL - 15 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12460700?dopt=Abstract ER - TY - JOUR T1 - Calcium channel blocker use and gastrointestinal tract bleeding among older adults. JF - Age Ageing Y1 - 2002 A1 - Kaplan, Robert C A1 - Heckbert, Susan R A1 - Koepsell, Thomas D A1 - Rosendaal, Frits R A1 - Furberg, Curt D A1 - Cooper, Lawton S A1 - Psaty, Bruce M KW - Aged KW - Antihypertensive Agents KW - Calcium Channel Blockers KW - Gastrointestinal Hemorrhage KW - Geriatric Assessment KW - Health Services for the Aged KW - Humans KW - Hypertension KW - Prospective Studies KW - Risk Factors VL - 31 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12006312?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular disease risk status in elderly persons with renal insufficiency. JF - Kidney Int Y1 - 2002 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Crump, Casey A1 - Bleyer, Anthony J A1 - Manolio, Teri A A1 - Tracy, Russell P A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Age Distribution KW - Aged KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Disease KW - Creatinine KW - Cross-Sectional Studies KW - Female KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Prevalence KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: 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.

VL - 62 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12164883?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. JF - Arch Intern Med Y1 - 2002 A1 - Tsai, Albert W A1 - Cushman, Mary A1 - Rosamond, Wayne D A1 - Heckbert, Susan R A1 - Polak, Joseph F A1 - Folsom, Aaron R KW - Aged KW - Arteriosclerosis KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Proportional Hazards Models KW - Prospective Studies KW - Pulmonary Embolism KW - Risk Factors KW - United States KW - Venous Thrombosis AB -

BACKGROUND: 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.

VL - 162 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12020191?dopt=Abstract ER - TY - JOUR T1 - Fasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Smith, Nicholas L A1 - Barzilay, Joshua I A1 - Shaffer, Douglas A1 - Savage, Peter J A1 - Heckbert, Susan R A1 - Kuller, Lewis H A1 - Kronmal, Richard A A1 - Resnick, Helaine E A1 - Psaty, Bruce M KW - Aged KW - Blood Glucose KW - Cardiovascular Diseases KW - Fasting KW - Female KW - Glucose Tolerance Test KW - Humans KW - Male KW - Myocardial Infarction KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Risk Assessment KW - Stroke AB -

BACKGROUND: 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.

VL - 162 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11802755?dopt=Abstract ER - TY - JOUR T1 - Glucose, blood pressure, and lipid control in older people with and without diabetes mellitus: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2002 A1 - Smith, Nicholas L A1 - Savage, Peter J A1 - Heckbert, Susan R A1 - Barzilay, Joshua I A1 - Bittner, Vera A A1 - Kuller, Lewis H A1 - Psaty, Bruce M KW - Age Factors KW - Aged KW - Blood Glucose KW - Blood Pressure KW - Cardiovascular Diseases KW - Cholesterol, LDL KW - Cross-Sectional Studies KW - Diabetes Complications KW - Diabetes Mellitus KW - Female KW - Humans KW - Male KW - Prevalence KW - Prospective Studies KW - Risk Factors AB -

OBJECTIVES: 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.

VL - 50 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11943034?dopt=Abstract ER - TY - JOUR T1 - Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. JF - Arterioscler Thromb Vasc Biol Y1 - 2002 A1 - Kuller, Lewis A1 - Arnold, Alice A1 - Tracy, Russell A1 - Otvos, James A1 - Burke, Greg A1 - Psaty, Bruce A1 - Siscovick, David A1 - Freedman, David S A1 - Kronmal, Richard KW - Aged KW - Aging KW - Cardiovascular System KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Health Status KW - Humans KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Lipoproteins, VLDL KW - Magnetic Resonance Spectroscopy KW - Male KW - Nuclear Magnetic Resonance, Biomolecular KW - Risk Factors KW - Sex Factors AB -

OBJECTIVES: 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.

VL - 22 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12117734?dopt=Abstract ER - TY - JOUR T1 - Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. JF - Ann Intern Med Y1 - 2002 A1 - Gottdiener, John S A1 - McClelland, Robyn L A1 - Marshall, Robert A1 - Shemanski, Lynn A1 - Furberg, Curt D A1 - Kitzman, Dalane W A1 - Cushman, Mary A1 - Polak, Joseph A1 - Gardin, Julius M A1 - Gersh, Bernard J A1 - Aurigemma, Gerard P A1 - Manolio, Teri A KW - Aged KW - Cause of Death KW - Echocardiography KW - Female KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Prevalence KW - Prognosis KW - Risk Factors KW - Stroke KW - Ventricular Dysfunction, Right KW - Ventricular Function, Left AB -

BACKGROUND: 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.

VL - 137 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12379062?dopt=Abstract ER - TY - JOUR T1 - A regression model for longitudinal change in the presence of measurement error. JF - Ann Epidemiol Y1 - 2002 A1 - Yanez, N David A1 - Kronmal, Richard A A1 - Shemanski, Lynn R A1 - Psaty, Bruce M KW - Aged KW - Bias KW - Coronary Disease KW - Humans KW - Lipoproteins KW - Models, Statistical KW - Regression Analysis KW - Risk Factors AB -

PURPOSE: 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.

VL - 12 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11750238?dopt=Abstract ER - TY - JOUR T1 - The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. JF - Br J Ophthalmol Y1 - 2002 A1 - Klein, Ronald A1 - Marino, Emily K A1 - Kuller, Lewis H A1 - Polak, Joseph F A1 - Tracy, Russell P A1 - Gottdiener, John S A1 - Burke, Gregory L A1 - Hubbard, Larry D A1 - Boineau, Robin KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Black People KW - Blood Pressure KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diabetic Retinopathy KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Odds Ratio KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Time Factors KW - White People AB -

AIMS: 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.

VL - 86 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11801510?dopt=Abstract ER - TY - JOUR T1 - Reproducibility of two approaches for assessing alcohol consumption among older adults. JF - Addiction Research and Theory Y1 - 2002 A1 - Crum, RM A1 - Puddey, I A1 - Gilbert, CG A1 - Fried, LP KW - alcohol KW - elderly KW - measurement KW - questionnaire AB - Objectives: 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. VL - 10 IS - 4 ER - TY - JOUR T1 - Serum potassium level and dietary potassium intake as risk factors for stroke. JF - Neurology Y1 - 2002 A1 - Green, D M A1 - Ropper, A H A1 - Kronmal, R A A1 - Psaty, B M A1 - Burke, G L KW - Aged KW - Cohort Studies KW - Confidence Intervals KW - Diuretics KW - Humans KW - Linear Models KW - Male KW - Potassium KW - Potassium, Dietary KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke AB -

BACKGROUND: 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.

VL - 59 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12177362?dopt=Abstract ER - TY - JOUR T1 - Therapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Lemaitre, Rozenn N A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Kronmal, Richard A A1 - Newman, Anne B A1 - Burke, Gregory L KW - Aged KW - Cholesterol, LDL KW - Coronary Disease KW - Female KW - Follow-Up Studies KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Hypercholesterolemia KW - Hypolipidemic Agents KW - Incidence KW - Male KW - Multivariate Analysis KW - Proportional Hazards Models KW - Risk Factors KW - United States AB -

BACKGROUND: 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.

VL - 162 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12076239?dopt=Abstract ER - TY - JOUR T1 - Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Psaty, Bruce M A1 - Manolio, Teri A A1 - Smith, Nicholas L A1 - Heckbert, Susan R A1 - Gottdiener, John S A1 - Burke, Gregory L A1 - Weissfeld, Joel A1 - Enright, Paul A1 - Lumley, Thomas A1 - Powe, Neil A1 - Furberg, Curt D KW - Age Factors KW - Aged KW - Antihypertensive Agents KW - Awareness KW - Cohort Studies KW - Drug Therapy KW - Female KW - Health Knowledge, Attitudes, Practice KW - Humans KW - Hypertension KW - Male KW - Prospective Studies KW - Time Factors AB -

BACKGROUND: 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.

VL - 162 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12418946?dopt=Abstract ER - TY - JOUR T1 - Weight-modification trials in older adults: what should the outcome measure be? JF - Curr Control Trials Cardiovasc Med Y1 - 2002 A1 - Diehr, Paula A1 - Newman, Anne B A1 - Jackson, Sharon A A1 - Kuller, Lewis A1 - Powe, Neil AB -

BACKGROUND: 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.

VL - 3 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11985775?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and carotid atherosclerosis in older adults: the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2003 A1 - Mukamal, Kenneth J A1 - Kronmal, Richard A A1 - Mittleman, Murray A A1 - O'Leary, Daniel H A1 - Polak, Joseph F A1 - Cushman, Mary A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - Cross-Sectional Studies KW - Female KW - Health Surveys KW - Humans KW - Longitudinal Studies KW - Male KW - Prospective Studies AB -

OBJECTIVE: 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.

VL - 23 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14563651?dopt=Abstract ER - TY - JOUR T1 - The association between time since last meal and blood pressure in older adults: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2003 A1 - Smith, Nicholas L A1 - Psaty, Bruce M A1 - Rutan, Gale H A1 - Lumley, Thomas A1 - Yanez, David A1 - Chaves, Paulo H M A1 - Kronmal, Richard A KW - Aged KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Eating KW - Female KW - Humans KW - Hypotension KW - Male KW - Postprandial Period KW - Prospective Studies KW - Risk Factors KW - Time Factors AB -

OBJECTIVES: 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.

VL - 51 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12757570?dopt=Abstract ER - TY - JOUR T1 - Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. JF - Circulation Y1 - 2003 A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Edwards, Karen L A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Tang, Zhonghua A1 - Durda, J Peter A1 - Kronmal, Richard A A1 - Tracy, Russell P KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Brain Ischemia KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - European Continental Ancestry Group KW - Follow-Up Studies KW - Gene Frequency KW - Humans KW - Incidence KW - Linkage Disequilibrium KW - Polymorphism, Genetic KW - Receptors, Adrenergic, beta-2 KW - Risk Assessment KW - Stroke KW - United States AB -

BACKGROUND: 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.

VL - 107 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12682000?dopt=Abstract ER - TY - JOUR T1 - C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. JF - Circulation Y1 - 2003 A1 - Cao, Jie J A1 - Thach, Chau A1 - Manolio, Teri A A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Chaves, Paulo H M A1 - Polak, Joseph F A1 - Sutton-Tyrrell, Kim A1 - Herrington, David M A1 - Price, Thomas R A1 - Cushman, Mary KW - Aged KW - Brain Ischemia KW - C-Reactive Protein KW - California KW - Carotid Arteries KW - Cohort Studies KW - Comorbidity KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Maryland KW - North Carolina KW - Odds Ratio KW - Pennsylvania KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Stroke KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

BACKGROUND: 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.

VL - 108 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12821545?dopt=Abstract ER - TY - JOUR T1 - Diabetes and sleep disturbances: findings from the Sleep Heart Health Study. JF - Diabetes Care Y1 - 2003 A1 - Resnick, Helaine E A1 - Redline, Susan A1 - Shahar, Eyal A1 - Gilpin, Adele A1 - Newman, Anne A1 - Walter, Robert A1 - Ewy, Gordon A A1 - Howard, Barbara V A1 - Punjabi, Naresh M KW - Aged KW - Diabetes Mellitus KW - Female KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Prevalence KW - Risk Factors KW - Sleep Apnea Syndromes KW - Sleep Apnea, Obstructive AB -

OBJECTIVE: 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.

VL - 26 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12610025?dopt=Abstract ER - TY - JOUR T1 - Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. JF - Circulation Y1 - 2003 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Crump, Casey A1 - Bleyer, Anthony J A1 - Manolio, Teri A A1 - Tracy, Russell P A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Aged KW - alpha-2-Antiplasmin KW - Biomarkers KW - Blood Coagulation Factors KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - Cross-Sectional Studies KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Fibrinolysin KW - Humans KW - Inflammation KW - Interleukin-6 KW - Male KW - Prospective Studies KW - Renal Insufficiency KW - Risk Factors AB -

BACKGROUND: 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.

VL - 107 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12515748?dopt=Abstract ER - TY - JOUR T1 - Hormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study. JF - J Womens Health (Larchmt) Y1 - 2003 A1 - Rea, Thomas D A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Cushman, Mary A1 - Meilahn, Elaine A1 - Olson, Jean L A1 - Lemaitre, Rozenn N A1 - Smith, Nicholas L A1 - Sotoodehnia, Nona A1 - Chaves, Paulo H M KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cohort Studies KW - Estrogen Replacement Therapy KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Life Style KW - Middle Aged KW - Multivariate Analysis KW - Obesity KW - Osteoporosis, Postmenopausal KW - Proportional Hazards Models KW - Prospective Studies KW - Risk KW - Risk Factors KW - United States KW - Women's Health AB -

BACKGROUND: 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.

VL - 12 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12804341?dopt=Abstract ER - TY - JOUR T1 - Inflammation as a risk factor for atrial fibrillation. JF - Circulation Y1 - 2003 A1 - Aviles, Ronnier J A1 - Martin, David O A1 - Apperson-Hansen, Carolyn A1 - Houghtaling, Penny L A1 - Rautaharju, Pentti A1 - Kronmal, Richard A A1 - Tracy, Russell P A1 - Van Wagoner, David R A1 - Psaty, Bruce M A1 - Lauer, Michael S A1 - Chung, Mina K KW - Aged KW - Atrial Fibrillation KW - C-Reactive Protein KW - Cross-Sectional Studies KW - Female KW - Humans KW - Inflammation KW - Longitudinal Studies KW - Male KW - Risk Factors AB -

BACKGROUND: 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.

VL - 108 IS - 24 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14623805?dopt=Abstract ER - TY - JOUR T1 - The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study. JF - Ophthalmology Y1 - 2003 A1 - Wong, Tien Yin A1 - Klein, Ronald A1 - Sharrett, A Richey A1 - Manolio, Teri A A1 - Hubbard, Larry D A1 - Marino, Emily K A1 - Kuller, Lewis A1 - Burke, Gregory A1 - Tracy, Russell P A1 - Polak, Joseph F A1 - Gottdiener, John S A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Coronary Artery Disease KW - Cross-Sectional Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Prevalence KW - Retinal Diseases KW - Retinal Vessels KW - Risk Factors KW - United States AB -

PURPOSE: 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.

VL - 110 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12689883?dopt=Abstract ER - TY - JOUR T1 - Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). JF - Am J Hematol Y1 - 2003 A1 - Tsai, Albert W A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Heckbert, Susan R A1 - Rosamond, Wayne D A1 - Aleksic, Nena A1 - Yanez, N David A1 - Psaty, Bruce M A1 - Folsom, Aaron R KW - Aged KW - Aging KW - Animals KW - Case-Control Studies KW - Cohort Studies KW - Factor V KW - Female KW - Genotype KW - Homocysteine KW - Humans KW - Longitudinal Studies KW - Male KW - Methylenetetrahydrofolate Reductase (NADPH2) KW - Middle Aged KW - Odds Ratio KW - Oxidoreductases Acting on CH-NH Group Donors KW - Polymorphism, Genetic KW - Prospective Studies KW - Risk Factors KW - Venous Thrombosis AB -

We 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.

VL - 72 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12605391?dopt=Abstract ER - TY - JOUR T1 - Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. JF - Am J Respir Crit Care Med Y1 - 2003 A1 - Sanders, Mark H A1 - Newman, Anne B A1 - Haggerty, Catherine L A1 - Redline, Susan A1 - Lebowitz, Michael A1 - Samet, Jonathan A1 - O'Connor, George T A1 - Punjabi, Naresh M A1 - Shahar, Eyal KW - Aged KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Humans KW - Male KW - Middle Aged KW - Oxyhemoglobins KW - Polysomnography KW - Prospective Studies KW - Pulmonary Disease, Chronic Obstructive KW - Sleep KW - Sleep Apnea, Obstructive KW - Spirometry KW - Vital Capacity AB -

Neither 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.

VL - 167 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12502472?dopt=Abstract ER - TY - JOUR T1 - Trajectories of health for older adults over time: accounting fully for death. JF - Ann Intern Med Y1 - 2003 A1 - Diehr, Paula A1 - Patrick, Donald L KW - Aged KW - Aging KW - Death KW - Geriatric Assessment KW - Health Status Indicators KW - Health Surveys KW - Humans KW - Time Factors AB -

The 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.

VL - 139 IS - 5 Pt 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12965968?dopt=Abstract ER - TY - JOUR T1 - Assessment of prolonged QT and JT intervals in ventricular conduction defects. JF - Am J Cardiol Y1 - 2004 A1 - Rautaharju, Pentti M A1 - Zhang, Zhu-Ming A1 - Prineas, Ron A1 - Heiss, Gerardo KW - Adult KW - Aged KW - Aged, 80 and over KW - Arrhythmias, Cardiac KW - Bundle-Branch Block KW - Electrocardiography KW - Female KW - Heart Ventricles KW - Humans KW - Male KW - Middle Aged AB -

The 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.

VL - 93 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15081446?dopt=Abstract ER - TY - JOUR T1 - The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2004 A1 - Psaty, Bruce M A1 - Anderson, Melissa A1 - Kronmal, Richard A A1 - Tracy, Russell P A1 - Orchard, Trevor A1 - Fried, Linda P A1 - Lumley, Thomas A1 - Robbins, John A1 - Burke, Greg A1 - Newman, Anne B A1 - Furberg, Curt D KW - African Americans KW - African Continental Ancestry Group KW - Aged KW - Female KW - Health Surveys KW - Humans KW - Incidence KW - Lipids KW - Male KW - Mortality KW - Myocardial Infarction KW - Population Surveillance KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

OBJECTIVES: 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.

VL - 52 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15450039?dopt=Abstract ER - TY - JOUR T1 - Barriers to health care access among the elderly and who perceives them. JF - Am J Public Health Y1 - 2004 A1 - Fitzpatrick, Annette L A1 - Powe, Neil R A1 - Cooper, Lawton S A1 - Ives, Diane G A1 - Robbins, John A KW - Aged KW - Aged, 80 and over KW - Chi-Square Distribution KW - Female KW - Health Behavior KW - Health Services Accessibility KW - Humans KW - Logistic Models KW - Male KW - Medicare KW - Patients KW - Surveys and Questionnaires KW - United States AB -

OBJECTIVES: 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.

VL - 94 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15451751?dopt=Abstract ER - TY - JOUR T1 - Fish intake and risk of incident atrial fibrillation. JF - Circulation Y1 - 2004 A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Rimm, Eric B A1 - Lemaitre, Rozenn N A1 - Burke, Gregory L A1 - Lyles, Mary F A1 - Lefkowitz, David A1 - Siscovick, David S KW - Aged KW - Animals KW - Atrial Fibrillation KW - Cardiotonic Agents KW - Cohort Studies KW - Cooking KW - Diet KW - Dietary Fats KW - Fatty Acids, Omega-3 KW - Fish Oils KW - Fishes KW - Follow-Up Studies KW - Humans KW - Incidence KW - Massachusetts KW - Proportional Hazards Models KW - Prospective Studies KW - Risk KW - Seafood KW - Tuna AB -

BACKGROUND: 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.

VL - 110 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15262826?dopt=Abstract ER - TY - JOUR T1 - Medications and cardiovascular health in older adults: room for improvement in prevention and treatment. JF - Am J Geriatr Cardiol Y1 - 2004 A1 - Rhoads, Caroline S A1 - Psaty, Bruce M A1 - Olson, Jean L A1 - Furberg, Curt D KW - Aged KW - Antihypertensive Agents KW - Atrial Fibrillation KW - Cardiovascular Diseases KW - Diabetes Mellitus KW - Health Knowledge, Attitudes, Practice KW - Heart Failure KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Hypolipidemic Agents KW - Risk Factors VL - 13 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15133419?dopt=Abstract ER - TY - JOUR T1 - Mesenteric artery disease in the elderly. JF - J Vasc Surg Y1 - 2004 A1 - Hansen, Kimberley J A1 - Wilson, David B A1 - Craven, Timothy E A1 - Pearce, Jeffrey D A1 - English, William P A1 - Edwards, Matthew S A1 - Ayerdi, Juan A1 - Burke, Gregory L KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Celiac Artery KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Mesenteric Arteries KW - Mesenteric Artery, Superior KW - Mesenteric Vascular Occlusion KW - Prevalence KW - Ultrasonography, Doppler, Duplex KW - Weight Loss AB -

PURPOSE: 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.

VL - 40 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15218461?dopt=Abstract ER - TY - JOUR T1 - The presence of frailty in elderly persons with chronic renal insufficiency. JF - Am J Kidney Dis Y1 - 2004 A1 - Shlipak, Michael G A1 - Stehman-Breen, Catherine A1 - Fried, Linda F A1 - Song, Xiao A1 - Siscovick, David A1 - Fried, Linda P A1 - Psaty, Bruce M A1 - Newman, Anne B KW - Activities of Daily Living KW - Aged KW - Cross-Sectional Studies KW - Female KW - Frail Elderly KW - Humans KW - Kidney Failure, Chronic KW - Male KW - United States AB -

BACKGROUND: 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.

VL - 43 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15112177?dopt=Abstract ER - TY - JOUR T1 - The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. JF - Am J Kidney Dis Y1 - 2004 A1 - Barzilay, Joshua I A1 - Peterson, Do A1 - Cushman, Mary A1 - Heckbert, Susan R A1 - Cao, Jie J A1 - Blaum, Caroline A1 - Tracy, Russell P A1 - Klein, Ronald A1 - Herrington, David M KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Biomarkers KW - Brachial Artery KW - Comorbidity KW - Coronary Disease KW - Cross-Sectional Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Hypertension KW - Inflammation KW - Logistic Models KW - Male KW - Multivariate Analysis KW - Odds Ratio KW - Risk Factors KW - Smoking KW - Ultrasonography AB -

BACKGROUND: 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.

VL - 44 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15211434?dopt=Abstract ER - TY - JOUR T1 - Respiratory muscle strength and the risk of incident cardiovascular events. JF - Thorax Y1 - 2004 A1 - van der Palen, J A1 - Rea, T D A1 - Manolio, T A A1 - Lumley, T A1 - Newman, A B A1 - Tracy, R P A1 - Enright, P L A1 - Psaty, B M KW - Cardiovascular Diseases KW - Female KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Humans KW - Male KW - Maximal Voluntary Ventilation KW - Prospective Studies KW - Respiratory Muscles KW - Risk Factors KW - Vital Capacity AB -

BACKGROUND: 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.

VL - 59 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15563706?dopt=Abstract ER - TY - JOUR T1 - Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists. JF - J Am Geriatr Soc Y1 - 2004 A1 - Bryson, Chris L A1 - Smith, Nicholas L A1 - Kuller, Lewis H A1 - Chaves, Paulo H M A1 - Manolio, Teri A A1 - Lewis, William A1 - Boyko, Edward J A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Adrenergic alpha-Antagonists KW - Aged KW - Antihypertensive Agents KW - Benzothiadiazines KW - Blood Pressure KW - Cohort Studies KW - Diuretics KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Male KW - Risk Factors KW - Sodium Chloride Symporter Inhibitors KW - United States AB -

OBJECTIVES: 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.

VL - 52 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15450040?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. JF - Am J Epidemiol Y1 - 2004 A1 - Punjabi, Naresh M A1 - Shahar, Eyal A1 - Redline, Susan A1 - Gottlieb, Daniel J A1 - Givelber, Rachel A1 - Resnick, Helaine E KW - Aged KW - Blood Gas Analysis KW - Body Constitution KW - Body Mass Index KW - Cohort Studies KW - Confounding Factors, Epidemiologic KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Intolerance KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Linear Models KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Oxyhemoglobins KW - Polysomnography KW - Research Design KW - Risk Factors KW - Severity of Illness Index KW - Sleep Apnea Syndromes AB -

Clinic-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.

VL - 160 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15353412?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study. JF - Sleep Y1 - 2004 A1 - Boland, Lori L A1 - Shahar, Eyal A1 - Wong, Tien Y A1 - Klein, Ronald A1 - Punjabi, Naresh A1 - Robbins, John A A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Coronary Disease KW - Cross-Sectional Studies KW - Female KW - Humans KW - Hypoxia KW - Middle Aged KW - Polysomnography KW - Positive-Pressure Respiration KW - Retina KW - Retinal Vessels KW - Sleep Apnea Syndromes AB -

STUDY 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.

VL - 27 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15164900?dopt=Abstract ER - TY - JOUR T1 - Survival associated with two sets of diagnostic criteria for congestive heart failure. JF - Am J Epidemiol Y1 - 2004 A1 - Schellenbaum, Gina D A1 - Rea, Thomas D A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Lumley, Thomas A1 - Roger, Veronique L A1 - Kitzman, Dalane W A1 - Taylor, Herman A A1 - Levy, Daniel A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Diagnosis, Differential KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Prognosis KW - Severity of Illness Index KW - Survival Analysis AB -

Congestive 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.

VL - 160 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15383406?dopt=Abstract ER - TY - JOUR T1 - Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure. JF - Am Heart J Y1 - 2004 A1 - Smith, Nicholas L A1 - Chan, Jeannie D A1 - Rea, Thomas D A1 - Wiggins, Kerri L A1 - Gottdiener, John S A1 - Lumley, Thomas A1 - Psaty, Bruce M KW - Adrenergic beta-Antagonists KW - Aged KW - Angiotensin II Type 1 Receptor Blockers KW - Angiotensin-Converting Enzyme Inhibitors KW - Cohort Studies KW - Drug Therapy KW - Drug Therapy, Combination KW - Female KW - Heart Failure KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence AB -

BACKGROUND: 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.

VL - 148 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15459605?dopt=Abstract ER - TY - JOUR T1 - Age-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. JF - Circulation Y1 - 2005 A1 - Haas, Donald C A1 - Foster, Gregory L A1 - Nieto, F Javier A1 - Redline, Susan A1 - Resnick, Helaine E A1 - Robbins, John A A1 - Young, Terry A1 - Pickering, Thomas G KW - Adult KW - Age Factors KW - Aged KW - Antihypertensive Agents KW - Cross-Sectional Studies KW - Diastole KW - Female KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Risk Factors KW - Sleep Apnea Syndromes KW - Sleep Apnea, Central KW - Systole AB -

BACKGROUND: 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.

VL - 111 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15699282?dopt=Abstract ER - TY - JOUR T1 - Association between screening for osteoporosis and the incidence of hip fracture. JF - Ann Intern Med Y1 - 2005 A1 - Kern, Lisa M A1 - Powe, Neil R A1 - Levine, Michael A A1 - Fitzpatrick, Annette L A1 - Harris, Tamara B A1 - Robbins, John A1 - Fried, Linda P KW - Absorptiometry, Photon KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Hip Fractures KW - Humans KW - Incidence KW - Male KW - Mass Screening KW - Osteoporosis KW - Risk Factors KW - Sensitivity and Specificity AB -

BACKGROUND: 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.

VL - 142 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15684205?dopt=Abstract ER - TY - JOUR T1 - Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS). JF - Am Heart J Y1 - 2005 A1 - Chan, Jeannie D A1 - Rea, Thomas D A1 - Smith, Nicholas L A1 - Siscovick, David A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Chaves, Paulo A1 - Furberg, Curt D A1 - Kuller, Lewis A1 - Psaty, Bruce M KW - Adrenergic beta-Antagonists KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Male AB -

BACKGROUND: 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.

VL - 150 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16169325?dopt=Abstract ER - TY - JOUR T1 - Association of sleep time with diabetes mellitus and impaired glucose tolerance. JF - Arch Intern Med Y1 - 2005 A1 - Gottlieb, Daniel J A1 - Punjabi, Naresh M A1 - Newman, Ann B A1 - Resnick, Helaine E A1 - Redline, Susan A1 - Baldwin, Carol M A1 - Nieto, F Javier KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Diabetes Mellitus KW - Disease Progression KW - Female KW - Glucose Intolerance KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Prevalence KW - Prospective Studies KW - Sleep KW - Surveys and Questionnaires KW - Time Factors KW - United States AB -

BACKGROUND: 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.

VL - 165 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15851636?dopt=Abstract ER - TY - JOUR T1 - beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2005 A1 - Hindorff, Lucia A A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Herrington, David M A1 - Edwards, Karen L A1 - Tracy, Russell P KW - African Americans KW - Antihypertensive Agents KW - Arteriosclerosis KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Homozygote KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Genetic KW - Receptors, Adrenergic, beta-2 KW - Risk Factors AB -

BACKGROUND: 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.

VL - 18 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15797659?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JF - JAMA Y1 - 2005 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Cushman, Mary A1 - Manolio, Teri A A1 - Peterson, Do A1 - Stehman-Breen, Catherine A1 - Bleyer, Anthony A1 - Newman, Anne A1 - Siscovick, David A1 - Psaty, Bruce KW - Aged KW - Cardiovascular Diseases KW - Chronic Disease KW - Humans KW - Kidney Diseases KW - Longitudinal Studies KW - Risk Factors AB -

CONTEXT: 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.

VL - 293 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15827312?dopt=Abstract ER - TY - JOUR T1 - Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. JF - Atherosclerosis Y1 - 2005 A1 - Reiner, Alexander P A1 - Diehr, Paula A1 - Browner, Warren S A1 - Humphries, Stephen E A1 - Jenny, Nancy S A1 - Cushman, Mary A1 - Tracy, Russell P A1 - Walston, Jeremy A1 - Lumley, Thomas A1 - Newman, Anne B A1 - Kuller, Lewis H A1 - Psaty, Bruce M KW - Aged KW - Aging KW - Carboxypeptidase B2 KW - Cause of Death KW - Cohort Studies KW - Female KW - Genotype KW - Health Status KW - Humans KW - Inflammation KW - Longevity KW - Male KW - Middle Aged KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Genetic KW - Promoter Regions, Genetic KW - Prospective Studies KW - Risk Factors KW - Thrombosis AB -

Inflammatory 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.

VL - 181 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15939070?dopt=Abstract ER - TY - JOUR T1 - C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. JF - Circulation Y1 - 2005 A1 - Cushman, Mary A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Manolio, Teri A A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Polak, Joseph F A1 - Tracy, Russell P KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Coronary Disease KW - Female KW - Humans KW - Incidence KW - Inflammation KW - Male KW - Myocardial Infarction KW - Predictive Value of Tests KW - Risk Factors AB -

BACKGROUND: 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.

VL - 112 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15983251?dopt=Abstract ER - TY - JOUR T1 - Cystatin C concentration as a risk factor for heart failure in older adults. JF - Ann Intern Med Y1 - 2005 A1 - Sarnak, Mark J A1 - Katz, Ronit A1 - Stehman-Breen, Catherine O A1 - Fried, Linda F A1 - Jenny, Nancy Swords A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Siscovick, David A1 - Shlipak, Michael G KW - Aged KW - Biomarkers KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Incidence KW - Kidney KW - Kidney Function Tests KW - Male KW - Risk Factors KW - United States AB -

BACKGROUND: 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.

VL - 142 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15809461?dopt=Abstract ER - TY - JOUR T1 - Cystatin-C and inflammatory markers in the ambulatory elderly. JF - Am J Med Y1 - 2005 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Cushman, Mary A1 - Sarnak, Mark J A1 - Stehman-Breen, Catherine A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Tracy, Russell P A1 - Newman, Anne A1 - Fried, Linda KW - Age Factors KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cross-Sectional Studies KW - Cystatin C KW - Cystatins KW - Female KW - Fibrinogen KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Male KW - Predictive Value of Tests KW - Sensitivity and Specificity AB -

PURPOSE: 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.

VL - 118 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16378798?dopt=Abstract ER - TY - JOUR T1 - Cystatin-C and mortality in elderly persons with heart failure. JF - J Am Coll Cardiol Y1 - 2005 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Fried, Linda F A1 - Jenny, Nancy Swords A1 - Stehman-Breen, Catherine O A1 - Newman, Anne B A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Sarnak, Mark J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Male KW - Pilot Projects KW - Predictive Value of Tests KW - Risk Assessment KW - Survival Analysis AB -

OBJECTIVES: 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.

VL - 45 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15653026?dopt=Abstract ER - TY - JOUR T1 - Incidence of cardiovascular disease in older Americans: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2005 A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Manolio, Teri A A1 - Fried, Linda P A1 - Robbins, John A A1 - Kronmal, Richard A KW - African Americans KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Geriatric Assessment KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Sex Distribution KW - Survival Rate KW - United States AB -

OBJECTIVES: 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.

VL - 53 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15673343?dopt=Abstract ER - TY - JOUR T1 - Methods for incorporating death into health-related variables in longitudinal studies. JF - J Clin Epidemiol Y1 - 2005 A1 - Diehr, Paula A1 - Johnson, Laura Lee A1 - Patrick, Donald L A1 - Psaty, Bruce KW - Activities of Daily Living KW - Death KW - Health Status Indicators KW - Humans KW - Longitudinal Studies KW - Proportional Hazards Models AB -

BACKGROUND 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.

VL - 58 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16223654?dopt=Abstract ER - TY - JOUR T1 - Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. JF - Am J Epidemiol Y1 - 2005 A1 - Podewils, Laura Jean A1 - Guallar, Eliseo A1 - Kuller, Lewis H A1 - Fried, Linda P A1 - Lopez, Oscar L A1 - Carlson, Michelle A1 - Lyketsos, Constantine G KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Apolipoproteins E KW - Dementia KW - Dementia, Vascular KW - Female KW - Genotype KW - Humans KW - Male KW - Motor Activity KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States AB -

Physical 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.

VL - 161 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15781953?dopt=Abstract ER - TY - JOUR T1 - Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. JF - Am J Hum Genet Y1 - 2005 A1 - Reiner, Alexander P A1 - Ziv, Elad A1 - Lind, Denise L A1 - Nievergelt, Caroline M A1 - Schork, Nicholas J A1 - Cummings, Steven R A1 - Phong, Angie A1 - Burchard, Esteban González A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Kwok, Pui-Yan KW - African Americans KW - Aged KW - Aging KW - Algorithms KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Genetics, Population KW - Genotype KW - Humans KW - Male KW - Models, Genetic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Socioeconomic Factors AB -

U.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.

VL - 76 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15660291?dopt=Abstract ER - TY - JOUR T1 - Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. JF - Cancer Y1 - 2005 A1 - Chen, Chu A1 - Lewis, S Kay A1 - Voigt, Lynda A1 - Fitzpatrick, Annette A1 - Plymate, Stephen R A1 - Weiss, Noel S KW - Aged KW - Aged, 80 and over KW - Carcinoma KW - Case-Control Studies KW - Humans KW - Hypoglycemic Agents KW - Incidence KW - Insulin KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Prostatic Neoplasms KW - Risk Factors AB -

BACKGROUND: 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.

VL - 103 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15540247?dopt=Abstract ER - TY - JOUR T1 - Renal duplex parameters, blood pressure, and renal function in elderly people. JF - Am J Kidney Dis Y1 - 2005 A1 - Pearce, Jeffrey D A1 - Edwards, Matthew S A1 - Craven, Timothy E A1 - English, William P A1 - Mondi, Matthew M A1 - Reavis, Scott W A1 - Hansen, Kimberley J KW - African Americans KW - Aged KW - Aging KW - Arteriosclerosis KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - Cross-Sectional Studies KW - Diastole KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension, Renovascular KW - Kidney KW - Kidney Diseases KW - Kidney Function Tests KW - Male KW - Renal Artery KW - Renal Artery Obstruction KW - Renal Circulation KW - Risk Factors KW - Sampling Studies KW - Systole KW - Ultrasonography, Doppler, Duplex KW - United States AB -

BACKGROUND: 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.

VL - 45 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15861349?dopt=Abstract ER - TY - JOUR T1 - Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2005 A1 - Kennedy, Margaret A1 - Solomon, Cam A1 - Manolio, Teri A A1 - Criqui, Michael H A1 - Newman, Anne B A1 - Polak, Joseph F A1 - Burke, Gregory L A1 - Enright, Paul A1 - Cushman, Mary KW - Aged KW - Aged, 80 and over KW - Ankle KW - Brachial Artery KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Peripheral Vascular Diseases KW - Risk Assessment KW - Risk Factors AB -

BACKGROUND: 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.

VL - 165 IS - 16 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16157835?dopt=Abstract ER - TY - JOUR T1 - Statin use and the risk of incident dementia: the Cardiovascular Health Study. JF - Arch Neurol Y1 - 2005 A1 - Rea, Thomas D A1 - Breitner, John C A1 - Psaty, Bruce M A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Newman, Anne B A1 - Hazzard, William R A1 - Zandi, Peter P A1 - Burke, Gregory L A1 - Lyketsos, Constantine G A1 - Bernick, Charles A1 - Kuller, Lewis H KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Hyperlipidemias KW - Male AB -

BACKGROUND: 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.

VL - 62 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16009757?dopt=Abstract ER - TY - JOUR T1 - Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly. JF - Neurology Y1 - 2005 A1 - Kaplan, R C A1 - Tirschwell, D L A1 - Longstreth, W T A1 - Manolio, T A A1 - Heckbert, S R A1 - Lefkowitz, D A1 - El-Saed, A A1 - Psaty, B M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Anticoagulants KW - Antihypertensive Agents KW - Brain Ischemia KW - Cohort Studies KW - Comorbidity KW - Coronary Artery Disease KW - Drug Utilization KW - Female KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Hypolipidemic Agents KW - Male KW - Mortality KW - Prospective Studies KW - Recurrence KW - Sex Factors KW - Stroke KW - Treatment Outcome AB -

BACKGROUND: 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.

VL - 65 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16186519?dopt=Abstract ER - TY - JOUR T1 - Weight loss, muscle strength, and angiotensin-converting enzyme inhibitors in older adults with congestive heart failure or hypertension. JF - J Am Geriatr Soc Y1 - 2005 A1 - Schellenbaum, Gina D A1 - Smith, Nicholas L A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rea, Thomas D A1 - Furberg, Curt D A1 - Lyles, Mary F A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Angiotensin-Converting Enzyme Inhibitors KW - Female KW - Hand Strength KW - Heart Failure KW - Humans KW - Hypertension KW - Male KW - Multivariate Analysis KW - Outcome Assessment, Health Care KW - Prospective Studies KW - Statistics as Topic KW - United States KW - Weight Loss AB -

OBJECTIVES: 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.

VL - 53 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16274385?dopt=Abstract ER - TY - JOUR T1 - 10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2006 A1 - Kuller, Lewis H A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Robbins, John A A1 - O'Leary, Daniel H A1 - Tracy, Russell P A1 - Burke, Gregory L A1 - Manolio, Teri A A1 - Chaves, Paolo H M KW - African Continental Ancestry Group KW - Aged KW - Blood Chemical Analysis KW - Cardiovascular Diseases KW - Comorbidity KW - Coronary Disease KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Prevalence KW - Proportional Hazards Models KW - Regression Analysis KW - Risk Factors KW - Sex Distribution KW - United States AB -

BACKGROUND: 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.

VL - 166 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16401813?dopt=Abstract ER - TY - JOUR T1 - African ancestry, socioeconomic status, and kidney function in elderly African Americans: a genetic admixture analysis. JF - J Am Soc Nephrol Y1 - 2006 A1 - Peralta, Carmen A A1 - Ziv, Elad A1 - Katz, Ronit A1 - Reiner, Alex A1 - Burchard, Esteban González A1 - Fried, Linda A1 - Kwok, Pui-Yan A1 - Psaty, Bruce A1 - Shlipak, Michael KW - African Americans KW - Aged KW - Creatinine KW - Cross-Sectional Studies KW - Cystatin C KW - Cystatins KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Linear Models KW - Longitudinal Studies KW - Male KW - Social Class AB -

Kidney 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.

VL - 17 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17082243?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2006 A1 - Mukamal, Kenneth J A1 - Chung, Hyoju A1 - Jenny, Nancy S A1 - Kuller, Lewis H A1 - Longstreth, W T A1 - Mittleman, Murray A A1 - Burke, Gregory L A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Apolipoproteins E KW - Beer KW - Cohort Studies KW - Coronary Disease KW - Female KW - Genotype KW - Health Behavior KW - Humans KW - Incidence KW - Male KW - Residence Characteristics KW - Risk Assessment KW - Socioeconomic Factors KW - United States KW - Wine AB -

OBJECTIVES: 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.

VL - 54 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16420195?dopt=Abstract ER - TY - JOUR T1 - The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2006 A1 - Cao, Jie J A1 - Barzilay, Joshua I A1 - Peterson, Do A1 - Manolio, Teri A A1 - Psaty, Bruce M A1 - Kuller, Lewis A1 - Wexler, Jason A1 - Bleyer, Anthony J A1 - Cushman, Mary KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Atherosclerosis KW - Cardiovascular Diseases KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Humans KW - Hypertension KW - Male KW - Peripheral Vascular Diseases KW - Prevalence KW - Risk Factors KW - Stroke KW - United States AB -

PURPOSE: 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.

VL - 187 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16242696?dopt=Abstract ER - TY - JOUR T1 - Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JF - JAMA Y1 - 2006 A1 - Lange, Leslie A A1 - Carlson, Christopher S A1 - Hindorff, Lucia A A1 - Lange, Ethan M A1 - Walston, Jeremy A1 - Durda, J Peter A1 - Cushman, Mary A1 - Bis, Joshua C A1 - Zeng, Donglin A1 - Lin, Danyu A1 - Kuller, Lewis H A1 - Nickerson, Deborah A A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Reiner, Alexander P KW - African Continental Ancestry Group KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Carotid Arteries KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Male KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk KW - Stroke KW - Tunica Intima AB -

CONTEXT: 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.

VL - 296 IS - 22 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17164456?dopt=Abstract ER - TY - JOUR T1 - Association of usual sleep duration with hypertension: the Sleep Heart Health Study. JF - Sleep Y1 - 2006 A1 - Gottlieb, Daniel J A1 - Redline, Susan A1 - Nieto, F Javier A1 - Baldwin, Carol M A1 - Newman, Anne B A1 - Resnick, Helaine E A1 - Punjabi, Naresh M KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Female KW - Health Surveys KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Odds Ratio KW - Prospective Studies KW - Sleep KW - Sleep Apnea, Obstructive KW - Sleep Deprivation KW - Statistics as Topic AB -

STUDY 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.

VL - 29 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16944668?dopt=Abstract ER - TY - JOUR T1 - Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. JF - Circulation Y1 - 2006 A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Vatta, Matteo A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Towbin, Jeffrey A A1 - Lemaitre, Rozenn N A1 - Rea, Thomas D A1 - Durda, J Peter A1 - Chang, Joel M A1 - Lumley, Thomas S A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Heckbert, Susan R KW - African Continental Ancestry Group KW - Aged KW - Case-Control Studies KW - Death, Sudden, Cardiac KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glutamine KW - Haplotypes KW - Homozygote KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Receptors, Adrenergic, beta-2 KW - Reproducibility of Results AB -

BACKGROUND: 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.

VL - 113 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16618831?dopt=Abstract ER - TY - JOUR T1 - Blood pressure level and outcomes in adults aged 65 and older with prior ischemic stroke. JF - J Am Geriatr Soc Y1 - 2006 A1 - Kaplan, Robert C A1 - Tirschwell, David L A1 - Longstreth, W T A1 - Manolio, Teri A A1 - Heckbert, Susan R A1 - LeValley, Aaron J A1 - Lefkowitz, David A1 - El-Saed, Aiman A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Brain Ischemia KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Outcome Assessment, Health Care KW - Prospective Studies KW - Recurrence KW - Stroke KW - Survival Rate AB -

OBJECTIVES: 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.

VL - 54 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16970636?dopt=Abstract ER - TY - JOUR T1 - Characteristics and baseline clinical predictors of future fatal versus nonfatal coronary heart disease events in older adults: the Cardiovascular Health Study. JF - Circulation Y1 - 2006 A1 - Pearte, Camille A A1 - Furberg, Curt D A1 - O'Meara, Ellen S A1 - Psaty, Bruce M A1 - Kuller, Lewis A1 - Powe, Neil R A1 - Manolio, Teri KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Carotid Artery, Common KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - Diabetes Mellitus KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Forecasting KW - Heart Failure KW - Heart Ventricles KW - Hospitalization KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Organ Size KW - Predictive Value of Tests KW - Risk Factors KW - Sampling Studies KW - Tunica Intima KW - Tunica Media KW - United States AB -

BACKGROUND: 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.

VL - 113 IS - 18 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16651468?dopt=Abstract ER - TY - JOUR T1 - Cigarette smoking and nocturnal sleep architecture. JF - Am J Epidemiol Y1 - 2006 A1 - Zhang, Lin A1 - Samet, Jonathan A1 - Caffo, Brian A1 - Punjabi, Naresh M KW - Aged KW - Arousal KW - Chi-Square Distribution KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Sleep Stages KW - Sleep Wake Disorders KW - Smoking KW - United States AB -

Cigarette 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.

VL - 164 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16829553?dopt=Abstract ER - TY - JOUR T1 - Comparison of mortality risk for electrocardiographic abnormalities in men and women with and without coronary heart disease (from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2006 A1 - Rautaharju, Pentti M A1 - Ge, Sijian A1 - Nelson, Jennifer C A1 - Marino Larsen, Emily K A1 - Psaty, Bruce M A1 - Furberg, Curt D A1 - Zhang, Zhu-Ming A1 - Robbins, John A1 - Gottdiener, John S A1 - Chaves, Paulo H M KW - Aged KW - Coronary Disease KW - Electrocardiography KW - Female KW - Humans KW - Male KW - Risk AB -

Mortality 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.

VL - 97 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16442387?dopt=Abstract ER - TY - JOUR T1 - Congestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses. JF - Ann Epidemiol Y1 - 2006 A1 - Schellenbaum, Gina D A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Rea, Thomas D A1 - Lumley, Thomas A1 - Kitzman, Dalane W A1 - Roger, Veronique L A1 - Taylor, Herman A A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Patient Discharge KW - Prognosis AB -

PURPOSE: 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.

VL - 16 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15964203?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. JF - Ann Intern Med Y1 - 2006 A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Newman, Anne B A1 - Stehman-Breen, Catherine A1 - Seliger, Stephen L A1 - Kestenbaum, Brian A1 - Psaty, Bruce A1 - Tracy, Russell P A1 - Siscovick, David S KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Cystatins KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Longitudinal Studies KW - Prognosis KW - Proportional Hazards Models KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

BACKGROUND: 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.

VL - 145 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16908914?dopt=Abstract ER - TY - JOUR T1 - Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. JF - J Am Coll Cardiol Y1 - 2006 A1 - Mozaffarian, Dariush A1 - Prineas, Ronald J A1 - Stein, Phyllis K A1 - Siscovick, David S KW - Aged KW - Animals KW - Atrioventricular Node KW - Cross-Sectional Studies KW - Diet KW - Electrocardiography KW - Fatty Acids, Omega-3 KW - Female KW - Fishes KW - Heart KW - Heart Rate KW - Humans KW - Male KW - Ventricular Function AB -

OBJECTIVES: 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.

VL - 48 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16875972?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation. JF - Metabolism Y1 - 2006 A1 - Miljkovic-Gacic, Iva A1 - Bunker, Clareann H A1 - Ferrell, Robert E A1 - Kammerer, Candace M A1 - Evans, Rhobert W A1 - Patrick, Alan L A1 - Kuller, Lewis H KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Alleles KW - Body Mass Index KW - Cardiovascular Diseases KW - Caribbean Region KW - Cohort Studies KW - DNA KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Humans KW - Lipase KW - Lipoproteins KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Liver KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Particle Size KW - Trinidad and Tobago KW - United States AB -

Despite 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.

VL - 55 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16324926?dopt=Abstract ER - TY - JOUR T1 - Mortality in pharmacologically treated older adults with diabetes: the Cardiovascular Health Study, 1989-2001. JF - PLoS Med Y1 - 2006 A1 - Kronmal, Richard A A1 - Barzilay, Joshua I A1 - Smith, Nicholas L A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Furberg, Curt KW - Administration, Oral KW - Aged KW - Cardiovascular Diseases KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Humans KW - Hypoglycemic Agents KW - Insulin KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Sex Distribution AB -

BACKGROUND: 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.

VL - 3 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17048978?dopt=Abstract ER - TY - JOUR T1 - New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study. JF - Diabetes Care Y1 - 2006 A1 - Smith, Nicholas L A1 - Barzilay, Joshua I A1 - Kronmal, Richard A1 - Lumley, Thomas A1 - Enquobahrie, Daniel A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Blood Glucose KW - Cardiovascular Diseases KW - Diabetes Complications KW - Diabetes Mellitus KW - Follow-Up Studies KW - Humans KW - Kaplan-Meier Estimate KW - Risk Factors KW - Survival Rate KW - Time Factors AB -

OBJECTIVE: 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.

VL - 29 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16936145?dopt=Abstract ER - TY - JOUR T1 - Obstructive sleep apnea and plasma natriuretic peptide levels in a community-based sample. JF - Sleep Y1 - 2006 A1 - Patwardhan, Anjali A A1 - Larson, Martin G A1 - Levy, Daniel A1 - Benjamin, Emelia J A1 - Leip, Eric P A1 - Keyes, Michelle J A1 - Wang, Thomas J A1 - Gottlieb, Daniel J A1 - Vasan, Ramachandran S KW - Atrial Fibrillation KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Natriuretic Peptides KW - Obesity KW - Polysomnography KW - Prevalence KW - Residence Characteristics KW - Severity of Illness Index KW - Sleep Apnea, Obstructive AB -

STUDY 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.

VL - 29 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17068983?dopt=Abstract ER - TY - JOUR T1 - The prevalence of the 65-kilodalton isoform of glutamic acid decarboxylase autoantibodies by glucose tolerance status in elderly patients from the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2006 A1 - Barinas-Mitchell, Emma A1 - Kuller, Lewis H A1 - Pietropaolo, Susan A1 - Zhang, Ying-Jian A1 - Henderson, Tyona A1 - Pietropaolo, Massimo KW - Aged KW - Aging KW - Autoantibodies KW - Blood Glucose KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Intolerance KW - Glutamate Decarboxylase KW - Humans KW - Insulin KW - Isoenzymes KW - Lipids KW - Logistic Models KW - Male KW - Nutrition Surveys AB -

CONTEXT: 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.

VL - 91 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16720660?dopt=Abstract ER - TY - JOUR T1 - Progression of atherosclerotic renovascular disease: A prospective population-based study. JF - J Vasc Surg Y1 - 2006 A1 - Pearce, Jeffrey D A1 - Craven, Brandon L A1 - Craven, Timothy E A1 - Piercy, K Todd A1 - Stafford, Jeanette M A1 - Edwards, Matthew S A1 - Hansen, Kimberley J KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Blood Flow Velocity KW - Blood Pressure KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - North Carolina KW - Population Surveillance KW - Prognosis KW - Prospective Studies KW - Renal Artery Obstruction KW - Severity of Illness Index KW - Time Factors KW - Ultrasonography, Doppler, Duplex AB -

OBJECTIVE: 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.

VL - 44 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16982169?dopt=Abstract ER - TY - JOUR T1 - The sensitivity and specificity of markers for event times. JF - Biostatistics Y1 - 2006 A1 - Cai, Tianxi A1 - Pepe, Margaret Sullivan A1 - Zheng, Yingye A1 - Lumley, Thomas A1 - Jenny, Nancy Swords KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Biometry KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Models, Statistical KW - Risk Factors KW - ROC Curve KW - Sensitivity and Specificity KW - Time Factors AB -

The 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.

VL - 7 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16079162?dopt=Abstract ER - TY - JOUR T1 - Sleep apnea in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the Sleep Heart Health Study. JF - J Am Soc Nephrol Y1 - 2006 A1 - Unruh, Mark L A1 - Sanders, Mark H A1 - Redline, Susan A1 - Piraino, Beth M A1 - Umans, Jason G A1 - Hammond, Terese C A1 - Sharief, Imran A1 - Punjabi, Naresh M A1 - Newman, Anne B KW - Blood Pressure KW - Body Mass Index KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Prevalence KW - Renal Dialysis KW - Severity of Illness Index KW - Sleep Apnea Syndromes AB -

Sleep-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.

VL - 17 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17082238?dopt=Abstract ER - TY - JOUR T1 - Soluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults. JF - J Thromb Haemost Y1 - 2006 A1 - Jenny, N S A1 - Arnold, A M A1 - Kuller, L H A1 - Sharrett, A R A1 - Fried, L P A1 - Psaty, B M A1 - Tracy, R P KW - Aged KW - Aged, 80 and over KW - Angina Pectoris KW - Biomarkers KW - Cardiovascular Diseases KW - Female KW - Humans KW - Incidence KW - Intercellular Adhesion Molecule-1 KW - Male KW - Mortality KW - Myocardial Infarction KW - Regression Analysis KW - Risk Factors KW - Sex Factors KW - Solubility KW - Stroke AB -

BACKGROUND: 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.

VL - 4 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16409459?dopt=Abstract ER - TY - JOUR T1 - Usefulness 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). JF - Am J Cardiol Y1 - 2006 A1 - Gardin, Julius M A1 - Arnold, Alice M A1 - Polak, Joseph A1 - Jackson, Sharon A1 - Smith, Vivienne A1 - Gottdiener, John KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aorta KW - Cardiovascular Diseases KW - Echocardiography, Doppler KW - Female KW - Heart Failure KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Multicenter Studies as Topic KW - Myocardial Infarction KW - Predictive Value of Tests KW - Risk Factors KW - Sex Factors KW - Stroke AB -

Echocardiographic 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.

VL - 97 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16442377?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and risk and prognosis of atrial fibrillation among older adults: the Cardiovascular Health Study. JF - Am Heart J Y1 - 2007 A1 - Mukamal, Kenneth J A1 - Psaty, Bruce M A1 - Rautaharju, Pentti M A1 - Furberg, Curt D A1 - Kuller, Lewis H A1 - Mittleman, Murray A A1 - Gottdiener, John S A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Atrial Fibrillation KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Prognosis KW - Risk Factors AB -

BACKGROUND: 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.

VL - 153 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17239687?dopt=Abstract ER - TY - JOUR T1 - Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. JF - Circulation Y1 - 2007 A1 - Cao, Jie J A1 - Arnold, Alice M A1 - Manolio, Teri A A1 - Polak, Joseph F A1 - Psaty, Bruce M A1 - Hirsch, Calvin H A1 - Kuller, Lewis H A1 - Cushman, Mary KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - Cohort Studies KW - Comorbidity KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Incidence KW - Inflammation KW - Kaplan-Meier Estimate KW - Male KW - Mass Screening KW - Mortality KW - Myocardial Infarction KW - Obesity KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - ROC Curve KW - Smoking KW - Stroke KW - Survival Analysis KW - Tunica Intima KW - Tunica Media KW - Ultrasonography KW - United States AB -

BACKGROUND: 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.

VL - 116 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17576871?dopt=Abstract ER - TY - JOUR T1 - Association 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. JF - J Clin Endocrinol Metab Y1 - 2007 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis H A1 - Strickler, Howard D A1 - Rohan, Tom E A1 - Cappola, Anne R A1 - Xue, XiaoNan A1 - Psaty, Bruce M KW - Aged KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Multivariate Analysis KW - Risk Factors KW - Stroke AB -

CONTEXT: 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.

VL - 92 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17264182?dopt=Abstract ER - TY - JOUR T1 - Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study. JF - J Am Coll Cardiol Y1 - 2007 A1 - Novaro, Gian M A1 - Katz, Ronit A1 - Aviles, Ronnier J A1 - Gottdiener, John S A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Otto, Catherine M A1 - Griffin, Brian P KW - Aged KW - Aged, 80 and over KW - Aortic Valve KW - Aortic Valve Stenosis KW - C-Reactive Protein KW - Calcinosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Heart Valve Diseases KW - Humans KW - Male KW - Risk Factors AB -

OBJECTIVES: 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.

VL - 50 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17996566?dopt=Abstract ER - TY - JOUR T1 - Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases. JF - Eur J Cardiovasc Prev Rehabil Y1 - 2007 A1 - Ballantyne, C A1 - Cushman, M A1 - Psaty, B A1 - Furberg, C A1 - Khaw, K T A1 - Sandhu, M A1 - Oldgren, J A1 - Rossi, G P A1 - Maiolino, G A1 - Cesari, M A1 - Lenzini, L A1 - James, S K A1 - Rimm, E A1 - Collins, R A1 - Anderson, J A1 - Koenig, W A1 - Brenner, H A1 - Rothenbacher, D A1 - Berglund, G A1 - Persson, M A1 - Berger, P A1 - Brilakis, E A1 - McConnell, J P A1 - Koenig, W A1 - Sacco, R A1 - Elkind, M A1 - Talmud, P A1 - Rimm, E A1 - Cannon, C P A1 - Packard, C A1 - Barrett-Connor, E A1 - Hofman, A A1 - Kardys, I A1 - Witteman, J C M A1 - Criqui, M A1 - Corsetti, J P A1 - Rainwater, D L A1 - Moss, A J A1 - Robins, S A1 - Bloomfield, H A1 - Collins, D A1 - Packard, C A1 - Wassertheil-Smoller, S A1 - Ridker, P A1 - Ballantyne, C A1 - Cannon, C P A1 - Cushman, M A1 - Danesh, J A1 - Gu, D A1 - Hofman, A A1 - Nelson, J J A1 - Thompson, S A1 - Zalewski, A A1 - Zariffa, N A1 - Di Angelantonio, E A1 - Kaptoge, S A1 - Thompson, A A1 - Thompson, S A1 - Walker, M A1 - Watson, S A1 - Wood, A KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Cardiovascular Diseases KW - Humans KW - Phospholipases A2 AB -

BACKGROUND: 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.

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17301621?dopt=Abstract ER - TY - JOUR T1 - The 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. JF - Eur J Epidemiol Y1 - 2007 A1 - Danesh, J A1 - Erqou, S A1 - Walker, M A1 - Thompson, S G A1 - Tipping, R A1 - Ford, C A1 - Pressel, S A1 - Walldius, G A1 - Jungner, I A1 - Folsom, A R A1 - Chambless, L E A1 - Knuiman, M A1 - Whincup, P H A1 - Wannamethee, S G A1 - Morris, R W A1 - Willeit, J A1 - Kiechl, S A1 - Santer, P A1 - Mayr, A A1 - Wald, N A1 - Ebrahim, S A1 - Lawlor, D A A1 - Yarnell, J W G A1 - Gallacher, J A1 - Casiglia, E A1 - Tikhonoff, V A1 - Nietert, P J A1 - Sutherland, S E A1 - Bachman, D L A1 - Keil, J E A1 - Cushman, M A1 - Psaty, B M A1 - Tracy, R P A1 - Tybjaerg-Hansen, A A1 - Nordestgaard, B G A1 - Frikke-Schmidt, R A1 - Giampaoli, S A1 - Palmieri, L A1 - Panico, S A1 - Vanuzzo, D A1 - Pilotto, L A1 - Simons, L A1 - McCallum, J A1 - Friedlander, Y A1 - Fowkes, F G R A1 - Lee, A J A1 - Smith, F B A1 - Taylor, J A1 - Guralnik, J A1 - Phillips, C A1 - Wallace, R A1 - Blazer, D A1 - Khaw, K T A1 - Jansson, J H A1 - Donfrancesco, C A1 - Salomaa, V A1 - Harald, K A1 - Jousilahti, P A1 - Vartiainen, E A1 - Woodward, M A1 - D'Agostino, R B A1 - Wolf, P A A1 - Vasan, R S A1 - Pencina, M J A1 - Bladbjerg, E M A1 - Jorgensen, T A1 - Moller, L A1 - Jespersen, J A1 - Dankner, R A1 - Chetrit, A A1 - Lubin, F A1 - Rosengren, A A1 - Wilhelmsen, L A1 - Lappas, G A1 - Eriksson, H A1 - Bjorkelund, C A1 - Cremer, P A1 - Nagel, D A1 - Tilvis, R A1 - Strandberg, T A1 - Rodriguez, B A1 - Bouter, L M A1 - Heine, R J A1 - Dekker, J M A1 - Nijpels, G A1 - Stehouwer, C D A A1 - Rimm, E A1 - Pai, J A1 - Sato, S A1 - Iso, H A1 - Kitamura, A A1 - Noda, H A1 - Goldbourt, U A1 - Salomaa, V A1 - Salonen, J T A1 - Nyyssönen, K A1 - Tuomainen, T-P A1 - Deeg, D A1 - Poppelaars, J L A1 - Meade, T A1 - Cooper, J A1 - Hedblad, B A1 - Berglund, G A1 - Engstrom, G A1 - Döring, A A1 - Koenig, W A1 - Meisinger, C A1 - Mraz, W A1 - Kuller, L A1 - Selmer, R A1 - Tverdal, A A1 - Nystad, W A1 - Gillum, R A1 - Mussolino, M A1 - Hankinson, S A1 - Manson, J A1 - De Stavola, B A1 - Knottenbelt, C A1 - Cooper, J A A1 - Bauer, K A A1 - Rosenberg, R D A1 - Sato, S A1 - Naito, Y A1 - Holme, I A1 - Nakagawa, H A1 - Miura, H A1 - Ducimetiere, P A1 - Jouven, X A1 - Crespo, C A1 - Garcia-Palmieri, M A1 - Amouyel, P A1 - Arveiler, D A1 - Evans, A A1 - Ferrieres, J A1 - Schulte, H A1 - Assmann, G A1 - Shepherd, J A1 - Packard, C A1 - Sattar, N A1 - Cantin, B A1 - Lamarche, B A1 - Després, J-P A1 - Dagenais, G R A1 - Barrett-Connor, E A1 - Wingard, D A1 - Bettencourt, R A1 - Gudnason, V A1 - Aspelund, T A1 - Sigurdsson, G A1 - Thorsson, B A1 - Trevisan, M A1 - Witteman, J A1 - Kardys, I A1 - Breteler, M A1 - Hofman, A A1 - Tunstall-Pedoe, H A1 - Tavendale, R A1 - Lowe, G D O A1 - Ben-Shlomo, Y A1 - Howard, B V A1 - Zhang, Y A1 - Best, L A1 - Umans, J A1 - Onat, A A1 - Meade, T W A1 - Njolstad, I A1 - Mathiesen, E A1 - Lochen, M L A1 - Wilsgaard, T A1 - Gaziano, J M A1 - Stampfer, M A1 - Ridker, P A1 - Ulmer, H A1 - Diem, G A1 - Concin, H A1 - Rodeghiero, F A1 - Tosetto, A A1 - Brunner, E A1 - Shipley, M A1 - Buring, J A1 - Cobbe, S M A1 - Ford, I A1 - Robertson, M A1 - He, Y A1 - Ibanez, A M A1 - Feskens, E J M A1 - Kromhout, D A1 - Collins, R A1 - Di Angelantonio, E A1 - Kaptoge, S A1 - Lewington, S A1 - Orfei, L A1 - Pennells, L A1 - Perry, P A1 - Ray, K A1 - Sarwar, N A1 - Scherman, M A1 - Thompson, A A1 - Watson, S A1 - Wensley, F A1 - White, I R A1 - Wood, A M KW - Albumins KW - Biomarkers KW - Cardiovascular Diseases KW - Databases, Factual KW - Far East KW - Humans KW - Inflammation KW - Leukocyte Count KW - Lipids KW - Lipoproteins, HDL KW - Prospective Studies KW - Risk Factors KW - Triglycerides AB -

Many 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.

VL - 22 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17876711?dopt=Abstract ER - TY - JOUR T1 - Gait variability and the risk of incident mobility disability in community-dwelling older adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2007 A1 - Brach, Jennifer S A1 - Studenski, Stephanie A A1 - Perera, Subashan A1 - VanSwearingen, Jessie M A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Gait KW - Gait Disorders, Neurologic KW - Humans KW - Male KW - Mobility Limitation KW - Prospective Studies KW - Risk Factors KW - Walking AB -

BACKGROUND: 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.

VL - 62 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17895436?dopt=Abstract ER - TY - JOUR T1 - IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. JF - Hum Genet Y1 - 2007 A1 - Walston, Jeremy D A1 - Fallin, M Daniele A1 - Cushman, Mary A1 - Lange, Leslie A1 - Psaty, Bruce A1 - Jenny, Nancy A1 - Browner, Warren A1 - Tracy, Russell A1 - Durda, Peter A1 - Reiner, Alex KW - African Americans KW - Aged KW - Alleles KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - Interleukin-6 KW - Introns KW - Longitudinal Studies KW - Male KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic AB -

Interleukin-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.

VL - 122 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17851695?dopt=Abstract ER - TY - JOUR T1 - Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study. JF - Soc Sci Med Y1 - 2007 A1 - Merkin, Sharon Stein A1 - Diez Roux, Ana V A1 - Coresh, Josef A1 - Fried, Linda F A1 - Jackson, Sharon A A1 - Powe, Neil R KW - Age Factors KW - Aged KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Kidney Failure, Chronic KW - Male KW - Proportional Hazards Models KW - Residence Characteristics KW - Risk Factors KW - Sex Factors KW - Social Class KW - United States AB -

Few 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.

VL - 65 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17499411?dopt=Abstract ER - TY - JOUR T1 - Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. JF - J Thromb Haemost Y1 - 2007 A1 - Zakai, N A A1 - Katz, R A1 - Jenny, N S A1 - Psaty, B M A1 - Reiner, A P A1 - Schwartz, S M A1 - Cushman, M KW - Aged KW - Aging KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol KW - Cohort Studies KW - Factor VIII KW - Female KW - Fibrinogen KW - Hemostasis KW - Homocysteine KW - Humans KW - Inflammation Mediators KW - Interleukin-6 KW - Leukocyte Count KW - Lipoprotein(a) KW - Male KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: 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.

VL - 5 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17388967?dopt=Abstract ER - TY - JOUR T1 - Inflammation biomarkers and near-term death in older men. JF - Am J Epidemiol Y1 - 2007 A1 - Jenny, Nancy Swords A1 - Yanez, N David A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Hirsch, Calvin H A1 - Tracy, Russell P KW - Age Distribution KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Diabetes Complications KW - Epidemiologic Studies KW - Female KW - Fibrinogen KW - Follow-Up Studies KW - Humans KW - Hypercholesterolemia KW - Hypertension KW - Inflammation KW - Male KW - Middle Aged KW - Obesity KW - Population Surveillance KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Risk Factors KW - Sex Distribution KW - Smoking KW - Time Factors KW - United States AB -

Associations 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.

VL - 165 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17215383?dopt=Abstract ER - TY - JOUR T1 - Kidney function, electrocardiographic findings, and cardiovascular events among older adults. JF - Clin J Am Soc Nephrol Y1 - 2007 A1 - Kestenbaum, Bryan A1 - Rudser, Kyle D A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Newman, Anne B A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Seliger, Stephen A1 - Stehman-Breen, Catherine A1 - Prineas, Ronald A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Cardiac Output, Low KW - Cardiovascular Diseases KW - Chronic Disease KW - Coronary Disease KW - Electrocardiography KW - Female KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Risk Assessment AB -

Chronic 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.

VL - 2 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17699457?dopt=Abstract ER - TY - JOUR T1 - Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. JF - Am J Epidemiol Y1 - 2007 A1 - Fitzpatrick, Annette L A1 - Kronmal, Richard A A1 - Gardner, Jeffrey P A1 - Psaty, Bruce M A1 - Jenny, Nancy S A1 - Tracy, Russell P A1 - Walston, Jeremy A1 - Kimura, Masyuki A1 - Aviv, Abraham KW - Aged KW - Cardiovascular Diseases KW - DNA KW - Female KW - Humans KW - Inflammation KW - Leukocytes KW - Male KW - Myocardial Infarction KW - Oxidative Stress KW - Pilot Projects KW - Polymorphism, Restriction Fragment Length KW - Risk KW - Risk Assessment KW - Risk Factors KW - Telomere AB -

The 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.

VL - 165 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17043079?dopt=Abstract ER - TY - JOUR T1 - Long-term costs and resource use in elderly participants with congestive heart failure in the Cardiovascular Health Study. JF - Am Heart J Y1 - 2007 A1 - Liao, Lawrence A1 - Anstrom, Kevin J A1 - Gottdiener, John S A1 - Pappas, Paul A A1 - Whellan, David J A1 - Kitzman, Dalane W A1 - Aurigemma, Gerard P A1 - Mark, Daniel B A1 - Schulman, Kevin A A1 - Jollis, James G KW - Aged KW - Costs and Cost Analysis KW - Female KW - Health Resources KW - Heart Failure KW - Humans KW - Male KW - Medicare KW - Prospective Studies KW - Time Factors AB -

BACKGROUND: 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.

VL - 153 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17239685?dopt=Abstract ER - TY - JOUR T1 - Physical activity and white matter lesion progression: assessment using MRI. JF - Neurology Y1 - 2007 A1 - Podewils, L J A1 - Guallar, E A1 - Beauchamp, N A1 - Lyketsos, C G A1 - Kuller, L H A1 - Scheltens, P KW - Activities of Daily Living KW - Aged KW - Alzheimer Disease KW - Cognition Disorders KW - Cohort Studies KW - Demyelinating Diseases KW - Disease Progression KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Motor Activity KW - United States AB -

We 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.

VL - 68 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17420407?dopt=Abstract ER - TY - JOUR T1 - Serum amyloid P and cardiovascular disease in older men and women: results from the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2007 A1 - Jenny, Nancy Swords A1 - Arnold, Alice M A1 - Kuller, Lewis H A1 - Tracy, Russell P A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Aging KW - Angina, Unstable KW - Atherosclerosis KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Case-Control Studies KW - Female KW - Humans KW - Hypertension KW - Immunity, Innate KW - Male KW - Myocardial Infarction KW - Obesity KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors KW - Serum Amyloid P-Component AB -

OBJECTIVE: 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.

VL - 27 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17138933?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and lower extremity arterial disease among older adults: the cardiovascular health study. JF - Am J Epidemiol Y1 - 2008 A1 - Mukamal, Kenneth J A1 - Kennedy, Margaret A1 - Cushman, Mary A1 - Kuller, Lewis H A1 - Newman, Anne B A1 - Polak, Joseph A1 - Criqui, Michael H A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Humans KW - Intermittent Claudication KW - Male KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Surveys and Questionnaires KW - Time Factors KW - United States AB -

Few 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.

VL - 167 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17971339?dopt=Abstract ER - TY - JOUR T1 - Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JF - JAMA Y1 - 2008 A1 - Fowkes, F G R A1 - Murray, G D A1 - Butcher, I A1 - Heald, C L A1 - Lee, R J A1 - Chambless, L E A1 - Folsom, A R A1 - Hirsch, A T A1 - Dramaix, M A1 - deBacker, G A1 - Wautrecht, J-C A1 - Kornitzer, M A1 - Newman, A B A1 - Cushman, M A1 - Sutton-Tyrrell, K A1 - Fowkes, F G R A1 - Lee, A J A1 - Price, J F A1 - D'Agostino, R B A1 - Murabito, J M A1 - Norman, P E A1 - Jamrozik, K A1 - Curb, J D A1 - Masaki, K H A1 - Rodríguez, B L A1 - Dekker, J M A1 - Bouter, L M A1 - Heine, R J A1 - Nijpels, G A1 - Stehouwer, C D A A1 - Ferrucci, L A1 - McDermott, M M A1 - Stoffers, H E A1 - Hooi, J D A1 - Knottnerus, J A A1 - Ogren, M A1 - Hedblad, B A1 - Witteman, J C A1 - Breteler, M M B A1 - Hunink, M G M A1 - Hofman, A A1 - Criqui, M H A1 - Langer, R D A1 - Fronek, A A1 - Hiatt, W R A1 - Hamman, R A1 - Resnick, H E A1 - Guralnik, J A1 - McDermott, M M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Ankle KW - Atherosclerosis KW - Blood Pressure KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Global Health KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - Severity of Illness Index AB -

CONTEXT: 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.

VL - 300 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18612117?dopt=Abstract ER - TY - JOUR T1 - Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2008 A1 - Shiffman, Dov A1 - O'Meara, Ellen S A1 - Bare, Lance A A1 - Rowland, Charles M A1 - Louie, Judy Z A1 - Arellano, Andre R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Iakoubova, Olga A1 - Luke, May M A1 - Young, Bradford A A1 - Malloy, Mary J A1 - Kane, John P A1 - Ellis, Stephen G A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Americans KW - Aged KW - Aged, 80 and over KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - United States AB -

OBJECTIVE: 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.

VL - 28 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17975119?dopt=Abstract ER - TY - JOUR T1 - Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. JF - Stroke Y1 - 2008 A1 - Fornage, Myriam A1 - Chiang, Y Aron A1 - O'Meara, Ellen S A1 - Psaty, Bruce M A1 - Reiner, Alexander P A1 - Siscovick, David S A1 - Tracy, Russell P A1 - Longstreth, W T KW - African Continental Ancestry Group KW - Aged KW - Biomarkers KW - Brain Infarction KW - C-Reactive Protein KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Haplotypes KW - Humans KW - Inflammation KW - Interleukin-6 KW - Magnetic Resonance Imaging KW - Male KW - Polymorphism, Single Nucleotide AB -

BACKGROUND 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.

VL - 39 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18436879?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2008 A1 - Cao, Jie J A1 - Biggs, Mary L A1 - Barzilay, Joshua A1 - Konen, Joseph A1 - Psaty, Bruce M A1 - Kuller, Lewis A1 - Bleyer, Anthony J A1 - Olson, Jean A1 - Wexler, Jason A1 - Summerson, John A1 - Cushman, Mary KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Biomarkers KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Female KW - Health Surveys KW - Humans KW - Male KW - Predictive Value of Tests KW - Risk AB -

BACKGROUND: 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.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17875308?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study. JF - Clin J Am Soc Nephrol Y1 - 2008 A1 - Mittalhenkle, Anuja A1 - Stehman-Breen, Catherine O A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Katz, Ronit A1 - Young, Bessie A A1 - Seliger, Stephen A1 - Gillen, Daniel A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Siscovick, David KW - Acute Kidney Injury KW - Aged KW - Cardiovascular Diseases KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND 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.

VL - 3 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18256380?dopt=Abstract ER - TY - JOUR T1 - Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2008 A1 - Hindorff, Lucia A A1 - Rice, Kenneth M A1 - Lange, Leslie A A1 - Diehr, Paula A1 - Halder, Indrani A1 - Walston, Jeremy A1 - Kwok, Pui A1 - Ziv, Elad A1 - Nievergelt, Caroline A1 - Cummings, Steven R A1 - Newman, Anne B A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Reiner, Alexander P KW - African Americans KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Linear Models KW - Longevity KW - Male KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - United States AB -

Common 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.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17888441?dopt=Abstract ER - TY - JOUR T1 - Cystatin C concentration as a predictor of systolic and diastolic heart failure. JF - J Card Fail Y1 - 2008 A1 - Moran, Andrew A1 - Katz, Ronit A1 - Smith, Nicolas L A1 - Fried, Linda F A1 - Sarnak, Mark J A1 - Seliger, Stephen L A1 - Psaty, Bruce A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cohort Studies KW - Confidence Intervals KW - Cystatin C KW - Cystatins KW - Echocardiography KW - Female KW - Heart Failure, Diastolic KW - Heart Failure, Systolic KW - Humans KW - Longitudinal Studies KW - Male KW - Predictive Value of Tests KW - Probability KW - Proportional Hazards Models KW - Risk Assessment KW - Sensitivity and Specificity KW - Stroke Volume KW - Survival Analysis AB -

BACKGROUND: 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.

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18226769?dopt=Abstract ER - TY - JOUR T1 - Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. JF - Circulation Y1 - 2008 A1 - Mozaffarian, Dariush A1 - Stein, Phyllis K A1 - Prineas, Ronald J A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Animals KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Electrocardiography KW - Fatty Acids, Omega-3 KW - Female KW - Fishes KW - Heart Rate KW - Humans KW - Male KW - Risk Factors KW - Seafood KW - Tuna KW - United States AB -

BACKGROUND: 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.

VL - 117 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18285566?dopt=Abstract ER - TY - JOUR T1 - Distribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2008 A1 - Furberg, Curt D A1 - Nelson, Jeanenne J A1 - Solomon, Cam A1 - Cushman, Mary A1 - Jenny, Nancy Swords A1 - Psaty, Bruce M KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Atherosclerosis KW - Body Mass Index KW - Cardiac Output, Low KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Cross-Sectional Studies KW - Electrocardiography KW - Female KW - Heart Failure KW - Humans KW - Hypertrophy, Left Ventricular KW - Long QT Syndrome KW - Male KW - Reference Values KW - Renal Insufficiency KW - Risk Factors KW - Statistics as Topic KW - Triglycerides AB -

OBJECTIVES: 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).

VL - 56 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18363676?dopt=Abstract ER - TY - JOUR T1 - Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. JF - Arch Neurol Y1 - 2008 A1 - Irie, Fumiko A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Peila, Rita A1 - Newman, Anne B A1 - Launer, Lenore J KW - African Americans KW - Age Factors KW - Aged KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Cognition KW - Cohort Studies KW - Confidence Intervals KW - Dementia, Vascular KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors AB -

BACKGROUND: 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.

VL - 65 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18195144?dopt=Abstract ER - TY - JOUR T1 - Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. JF - Sleep Y1 - 2008 A1 - Stamatakis, Katherine A1 - Sanders, Mark H A1 - Caffo, Brian A1 - Resnick, Helaine E A1 - Gottlieb, Dan J A1 - Mehra, Reena A1 - Punjabi, Naresh M KW - Aged KW - Blood Glucose KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Oxygen KW - Oxyhemoglobins KW - Polysomnography KW - Reference Values KW - Sleep Apnea, Obstructive AB -

STUDY 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.

VL - 31 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18652097?dopt=Abstract ER - TY - JOUR T1 - High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly. JF - Am Heart J Y1 - 2008 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Cappola, Anne R A1 - Xue, XiaoNan A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: 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.

VL - 155 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18513511?dopt=Abstract ER - TY - JOUR T1 - Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults. JF - Growth Horm IGF Res Y1 - 2008 A1 - Rajpathak, Swapnil N A1 - McGinn, Aileen P A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Pollak, Michael A1 - Cappola, Anne R A1 - Kuller, Lewis A1 - Xue, XiaoNan A1 - Newman, Anne B A1 - Strotmeyer, Elsa S A1 - Psaty, Bruce M A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Glucose Intolerance KW - Humans KW - Inflammation KW - Insulin-Like Growth Factor Binding Proteins KW - Male KW - Signal Transduction KW - Somatomedins AB -

Increasing 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.

VL - 18 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17904401?dopt=Abstract ER - TY - JOUR T1 - Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. JF - Ann Intern Med Y1 - 2008 A1 - Roddam, Andrew W A1 - Allen, Naomi E A1 - Appleby, Paul A1 - Key, Timothy J A1 - Ferrucci, Luigi A1 - Carter, H Ballentine A1 - Metter, E Jeffrey A1 - Chen, Chu A1 - Weiss, Noel S A1 - Fitzpatrick, Annette A1 - Hsing, Ann W A1 - Lacey, James V A1 - Helzlsouer, Kathy A1 - Rinaldi, Sabina A1 - Riboli, Elio A1 - Kaaks, Rudolf A1 - Janssen, Joop A M J L A1 - Wildhagen, Mark F A1 - Schröder, Fritz H A1 - Platz, Elizabeth A A1 - Pollak, Michael A1 - Giovannucci, Edward A1 - Schaefer, Catherine A1 - Quesenberry, Charles P A1 - Vogelman, Joseph H A1 - Severi, Gianluca A1 - English, Dallas R A1 - Giles, Graham G A1 - Stattin, Pär A1 - Hallmans, Göran A1 - Johansson, Mattias A1 - Chan, June M A1 - Gann, Peter A1 - Oliver, Steven E A1 - Holly, Jeff M A1 - Donovan, Jenny A1 - Meyer, François A1 - Bairati, Isabelle A1 - Galan, Pilar KW - Aged KW - Humans KW - Insulin-Like Growth Factor Binding Protein 2 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor Binding Proteins KW - Insulin-Like Growth Factor I KW - Insulin-Like Growth Factor II KW - Male KW - Middle Aged KW - Prospective Studies KW - Prostatic Neoplasms KW - Risk Factors KW - Somatomedins AB -

BACKGROUND: 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.

VL - 149 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18838726?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults. JF - Am J Hematol Y1 - 2008 A1 - Olson, Nels A1 - O'Meara, Ellen S A1 - Jenny, Nancy S A1 - Folsom, Aaron R A1 - Bovill, Edwin G A1 - Furberg, Curt D A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Cushman, Mary KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Female KW - Humans KW - Male KW - Risk Factors KW - Venous Thrombosis AB -

Lipoprotein-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.

VL - 83 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18383322?dopt=Abstract ER - TY - JOUR T1 - Metabolic syndrome and mortality in older adults: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2008 A1 - Mozaffarian, Dariush A1 - Kamineni, Aruna A1 - Prineas, Ronald J A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Fasting KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Male KW - Metabolic Syndrome KW - Multivariate Analysis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - United States AB -

BACKGROUND: 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.

VL - 168 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18474761?dopt=Abstract ER - TY - JOUR T1 - No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. JF - Neurology Y1 - 2008 A1 - Szekely, C A A1 - Green, R C A1 - Breitner, J C S A1 - Østbye, T A1 - Beiser, A S A1 - Corrada, M M A1 - Dodge, H H A1 - Ganguli, M A1 - Kawas, C H A1 - Kuller, L H A1 - Psaty, B M A1 - Resnick, S M A1 - Wolf, P A A1 - Zonderman, A B A1 - Welsh-Bohmer, K A A1 - Zandi, P P KW - Acetaminophen KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Amyloid beta-Peptides KW - Analgesics, Non-Narcotic KW - Anti-Inflammatory Agents, Non-Steroidal KW - Aspirin KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Neuroprotective Agents KW - Peptide Fragments KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

INTRODUCTION: 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.

VL - 70 IS - 24 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18509093?dopt=Abstract ER - TY - JOUR T1 - NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. JF - Neurology Y1 - 2008 A1 - Szekely, C A A1 - Breitner, J C S A1 - Fitzpatrick, A L A1 - Rea, T D A1 - Psaty, B M A1 - Kuller, L H A1 - Zandi, P P KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Anti-Inflammatory Agents, Non-Steroidal KW - Apolipoproteins E KW - Cardiovascular System KW - Dementia KW - Female KW - Humans KW - Incidence KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: 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.

VL - 70 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18003940?dopt=Abstract ER - TY - JOUR T1 - Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study. JF - Circulation Y1 - 2008 A1 - Mozaffarian, Dariush A1 - Furberg, Curt D A1 - Psaty, Bruce M A1 - Siscovick, David KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Exercise KW - Female KW - Humans KW - Incidence KW - Leisure Activities KW - Male KW - Motor Activity KW - Prospective Studies KW - Walking AB -

BACKGROUND: 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.

VL - 118 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18678768?dopt=Abstract ER - TY - JOUR T1 - Power spectral analysis of EEG activity during sleep in cigarette smokers. JF - Chest Y1 - 2008 A1 - Zhang, Lin A1 - Samet, Jonathan A1 - Caffo, Brian A1 - Bankman, Isaac A1 - Punjabi, Naresh M KW - Electroencephalography KW - Female KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Polysomnography KW - Sleep KW - Smoking KW - Spectroscopy, Fourier Transform Infrared AB -

BACKGROUND: 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.

VL - 133 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17925420?dopt=Abstract ER - TY - JOUR T1 - Prevalence, prognosis, and implications of isolated minor nonspecific ST-segment and T-wave abnormalities in older adults: Cardiovascular Health Study. JF - Circulation Y1 - 2008 A1 - Kumar, Anita A1 - Prineas, Ronald J A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Furberg, Curt D A1 - Robbins, John A1 - Lloyd-Jones, Donald M KW - Age Factors KW - Aged KW - Arrhythmias, Cardiac KW - Cardiovascular Diseases KW - Cohort Studies KW - Electrocardiography KW - Female KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Prevalence KW - Prognosis KW - Prospective Studies AB -

BACKGROUND: 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.

VL - 118 IS - 25 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19064684?dopt=Abstract ER - TY - JOUR T1 - Relation of sleep-disordered breathing to carotid plaque and intima-media thickness. JF - Atherosclerosis Y1 - 2008 A1 - Wattanakit, Keattiyoat A1 - Boland, Lori A1 - Punjabi, Naresh M A1 - Shahar, Eyal KW - Aged KW - Carotid Arteries KW - Carotid Artery Diseases KW - Female KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Risk Factors KW - Sleep Apnea Syndromes KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

BACKGROUND: 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.

VL - 197 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17433330?dopt=Abstract ER - TY - JOUR T1 - The relationship between exercise and risk of venous thrombosis in elderly people. JF - J Am Geriatr Soc Y1 - 2008 A1 - van Stralen, Karlijn J A1 - Doggen, Carine J M A1 - Lumley, Thomas A1 - Cushman, Mary A1 - Folsom, Aaron R A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Rosendaal, Frits R A1 - Heckbert, Susan R KW - Aged KW - Aged, 80 and over KW - Case-Control Studies KW - Cohort Studies KW - Energy Metabolism KW - Exercise KW - Female KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - United States KW - Venous Thrombosis AB -

OBJECTIVES: 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.

VL - 56 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18179500?dopt=Abstract ER - TY - JOUR T1 - The reliability and validity of measures of gait variability in community-dwelling older adults. JF - Arch Phys Med Rehabil Y1 - 2008 A1 - Brach, Jennifer S A1 - Perera, Subashan A1 - Studenski, Stephanie A1 - Newman, Anne B KW - Activities of Daily Living KW - Aged KW - Cross-Sectional Studies KW - Disability Evaluation KW - Exercise KW - Female KW - Gait KW - Health Status KW - Humans KW - Male KW - Pennsylvania KW - Rehabilitation KW - Reproducibility of Results AB -

OBJECTIVE: 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.

VL - 89 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19061741?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. JF - Am J Respir Crit Care Med Y1 - 2008 A1 - Punjabi, Naresh M A1 - Newman, Anne B A1 - Young, Terry B A1 - Resnick, Helaine E A1 - Sanders, Mark H KW - Aged KW - Apnea KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Oxyhemoglobins KW - Polysomnography KW - Sleep Apnea Syndromes KW - Terminology as Topic AB -

RATIONALE: 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.

VL - 177 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18276938?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study. JF - Diabetes Care Y1 - 2008 A1 - Seicean, Sinziana A1 - Kirchner, H Lester A1 - Gottlieb, Daniel J A1 - Punjabi, Naresh M A1 - Resnick, Helaine A1 - Sanders, Mark A1 - Budhiraja, Rohit A1 - Singer, Mendel A1 - Redline, Susan KW - Aged KW - Aged, 80 and over KW - Body Weight KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Female KW - Glucose Intolerance KW - Glucose Tolerance Test KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Overweight KW - Polysomnography KW - Reference Values KW - Sleep Wake Disorders AB -

OBJECTIVE: 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.

VL - 31 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18268072?dopt=Abstract ER - TY - JOUR T1 - Stance time and step width variability have unique contributing impairments in older persons. JF - Gait Posture Y1 - 2008 A1 - Brach, Jennifer S A1 - Studenski, Stephanie A1 - Perera, Subashan A1 - VanSwearingen, Jessie M A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Biomechanical Phenomena KW - Female KW - Gait Disorders, Neurologic KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Postural Balance KW - Range of Motion, Articular KW - Risk Factors KW - Signal Processing, Computer-Assisted AB -

Gait 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.

VL - 27 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17632004?dopt=Abstract ER - TY - JOUR T1 - Subjective and objective sleep quality in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study. JF - Am J Kidney Dis Y1 - 2008 A1 - Unruh, Mark L A1 - Sanders, Mark H A1 - Redline, Susan A1 - Piraino, Beth M A1 - Umans, Jason G A1 - Chami, Hassan A1 - Budhiraja, Rohit A1 - Punjabi, Naresh M A1 - Buysse, Daniel A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cross-Sectional Studies KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Heart Rate KW - Humans KW - Incidence KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Odds Ratio KW - Pennsylvania KW - Polysomnography KW - Prognosis KW - Renal Dialysis KW - Retrospective Studies KW - Risk Factors KW - Severity of Illness Index KW - Sleep KW - Sleep Apnea Syndromes KW - Surveys and Questionnaires AB -

BACKGROUND: 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.

VL - 52 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18617308?dopt=Abstract ER - TY - JOUR T1 - Total insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults. JF - J Am Geriatr Soc Y1 - 2008 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Xue, XiaoNan A1 - Kritchevsky, Stephen B A1 - Newman, Anne B A1 - Psaty, Bruce M KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Enzyme-Linked Immunosorbent Assay KW - Fasting KW - Female KW - Follow-Up Studies KW - Hand Strength KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Middle Aged KW - Prognosis KW - Prospective Studies KW - Risk Factors KW - Survival Rate KW - United States KW - Walking AB -

OBJECTIVES: 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.

VL - 56 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18312313?dopt=Abstract ER - TY - JOUR T1 - Agreement between nosologist and cardiovascular health study review of deaths: implications of coding differences. JF - J Am Geriatr Soc Y1 - 2009 A1 - Ives, Diane G A1 - Samuel, Paulraj A1 - Psaty, Bruce M A1 - Kuller, Lewis H KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Coronary Disease KW - Death Certificates KW - Female KW - Forms and Records Control KW - Humans KW - Longitudinal Studies KW - Male KW - Stroke AB -

OBJECTIVES: 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.

VL - 57 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19016930?dopt=Abstract ER - TY - JOUR T1 - Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2009 A1 - Sink, Kaycee M A1 - Leng, Xiaoyan A1 - Williamson, Jeff A1 - Kritchevsky, Stephen B A1 - Yaffe, Kristine A1 - Kuller, Lewis A1 - Yasar, Sevil A1 - Atkinson, Hal A1 - Robbins, Mike A1 - Psaty, Bruce A1 - Goff, David C KW - Aged KW - Angiotensin-Converting Enzyme Inhibitors KW - Blood-Brain Barrier KW - Cognition KW - Dementia KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: 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.

VL - 169 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597068?dopt=Abstract ER - TY - JOUR T1 - Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. JF - Aging Cell Y1 - 2009 A1 - Pawlikowska, Ludmila A1 - Hu, Donglei A1 - Huntsman, Scott A1 - Sung, Andrew A1 - Chu, Catherine A1 - Chen, Justin A1 - Joyner, Alexander H A1 - Schork, Nicholas J A1 - Hsueh, Wen-Chi A1 - Reiner, Alexander P A1 - Psaty, Bruce M A1 - Atzmon, Gil A1 - Barzilai, Nir A1 - Cummings, Steven R A1 - Browner, Warren S A1 - Kwok, Pui-Yan A1 - Ziv, Elad KW - Aged KW - Aged, 80 and over KW - Female KW - Follow-Up Studies KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome, Human KW - Genotype KW - Humans KW - Insulin KW - Insulin-Like Growth Factor I KW - Longevity KW - Male KW - Osteoporosis KW - Polymorphism, Single Nucleotide KW - Proto-Oncogene Proteins c-akt KW - Signal Transduction AB -

The 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.

VL - 8 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19489743?dopt=Abstract ER - TY - JOUR T1 - Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Dehghan, Abbas A1 - Yang, Qiong A1 - Peters, Annette A1 - Basu, Saonli A1 - Bis, Joshua C A1 - Rudnicka, Alicja R A1 - Kavousi, Maryam A1 - Chen, Ming-Huei A1 - Baumert, Jens A1 - Lowe, Gordon D O A1 - McKnight, Barbara A1 - Tang, Weihong A1 - de Maat, Moniek A1 - Larson, Martin G A1 - Eyhermendy, Susana A1 - McArdle, Wendy L A1 - Lumley, Thomas A1 - Pankow, James S A1 - Hofman, Albert A1 - Massaro, Joseph M A1 - Rivadeneira, Fernando A1 - Kolz, Melanie A1 - Taylor, Kent D A1 - van Duijn, Cornelia M A1 - Kathiresan, Sekar A1 - Illig, Thomas A1 - Aulchenko, Yurii S A1 - Volcik, Kelly A A1 - Johnson, Andrew D A1 - Uitterlinden, André G A1 - Tofler, Geoffrey H A1 - Gieger, Christian A1 - Psaty, Bruce M A1 - Couper, David J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C A1 - Strachan, David P A1 - Smith, Nicholas L A1 - Folsom, Aaron R KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

BACKGROUND: 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.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract ER - TY - JOUR T1 - Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2009 A1 - Jenny, Nancy Swords A1 - Arnold, Alice M A1 - Kuller, Lewis H A1 - Tracy, Russell P A1 - Psaty, Bruce M KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Case-Control Studies KW - Female KW - Health Surveys KW - Humans KW - Inflammation Mediators KW - Linear Models KW - Male KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Serum Amyloid P-Component KW - Time Factors KW - United States KW - Up-Regulation AB -

OBJECTIVE: 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.

VL - 29 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19164811?dopt=Abstract ER - TY - JOUR T1 - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Psaty, Bruce M A1 - O'Donnell, Christopher J A1 - Gudnason, Vilmundur A1 - Lunetta, Kathryn L A1 - Folsom, Aaron R A1 - Rotter, Jerome I A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Witteman, Jacqueline C M A1 - Boerwinkle, Eric KW - Adult KW - Aged KW - Aging KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Diseases KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Phenotype KW - Research Design KW - Risk Factors AB -

BACKGROUND: 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.

VL - 2 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031568?dopt=Abstract ER - TY - JOUR T1 - Common variants at ten loci influence QT interval duration in the QTGEN Study. JF - Nat Genet Y1 - 2009 A1 - Newton-Cheh, Christopher A1 - Eijgelsheim, Mark A1 - Rice, Kenneth M A1 - de Bakker, Paul I W A1 - Yin, Xiaoyan A1 - Estrada, Karol A1 - Bis, Joshua C A1 - Marciante, Kristin A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Sotoodehnia, Nona A1 - Smith, Nicholas L A1 - Rotter, Jerome I A1 - Kors, Jan A A1 - Witteman, Jacqueline C M A1 - Hofman, Albert A1 - Heckbert, Susan R A1 - O'Donnell, Christopher J A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Larson, Martin G A1 - Stricker, Bruno H Ch KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Chromosome Mapping KW - Death, Sudden, Cardiac KW - Electroencephalography KW - ERG1 Potassium Channel KW - Ether-A-Go-Go Potassium Channels KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome, Human KW - Humans KW - KCNQ1 Potassium Channel KW - Meta-Analysis as Topic KW - Muscle Proteins KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Voltage-Gated KW - Risk Factors KW - Sodium Channels AB -

QT 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.

VL - 41 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19305408?dopt=Abstract ER - TY - JOUR T1 - C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older. JF - Cancer Causes Control Y1 - 2009 A1 - Pierce, Brandon L A1 - Biggs, Mary L A1 - DeCambre, Marvalyn A1 - Reiner, Alexander P A1 - Li, Christopher A1 - Fitzpatrick, Annette A1 - Carlson, Christopher S A1 - Stanford, Janet L A1 - Austin, Melissa A KW - African Americans KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - European Continental Ancestry Group KW - Humans KW - Inflammation KW - Interleukin-6 KW - Male KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Prostatic Neoplasms KW - Risk Factors AB -

Inflammation 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.

VL - 20 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19267250?dopt=Abstract ER - TY - JOUR T1 - External validity of the cardiovascular health study: a comparison with the Medicare population. JF - Med Care Y1 - 2009 A1 - DiMartino, Lisa D A1 - Hammill, Bradley G A1 - Curtis, Lesley H A1 - Gottdiener, John S A1 - Manolio, Teri A A1 - Powe, Neil R A1 - Schulman, Kevin A KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Humans KW - Male KW - Medicare KW - Randomized Controlled Trials as Topic KW - Reproducibility of Results KW - Socioeconomic Factors KW - United States AB -

BACKGROUND: 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.

VL - 47 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597373?dopt=Abstract ER - TY - JOUR T1 - Gene variants associated with ischemic stroke: the cardiovascular health study. JF - Stroke Y1 - 2009 A1 - Luke, May M A1 - O'Meara, Ellen S A1 - Rowland, Charles M A1 - Shiffman, Dov A1 - Bare, Lance A A1 - Arellano, Andre R A1 - Longstreth, W T A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Brain Ischemia KW - Cardiovascular Diseases KW - Coronary Disease KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Variation KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND 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.

VL - 40 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19023099?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. JF - JAMA Y1 - 2009 A1 - Vasan, Ramachandran S A1 - Glazer, Nicole L A1 - Felix, Janine F A1 - Lieb, Wolfgang A1 - Wild, Philipp S A1 - Felix, Stephan B A1 - Watzinger, Norbert A1 - Larson, Martin G A1 - Smith, Nicholas L A1 - Dehghan, Abbas A1 - Grosshennig, Anika A1 - Schillert, Arne A1 - Teumer, Alexander A1 - Schmidt, Reinhold A1 - Kathiresan, Sekar A1 - Lumley, Thomas A1 - Aulchenko, Yurii S A1 - König, Inke R A1 - Zeller, Tanja A1 - Homuth, Georg A1 - Struchalin, Maksim A1 - Aragam, Jayashri A1 - Bis, Joshua C A1 - Rivadeneira, Fernando A1 - Erdmann, Jeanette A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Zweiker, Robert A1 - Lind, Lars A1 - Rodeheffer, Richard J A1 - Greiser, Karin Halina A1 - Levy, Daniel A1 - Haritunians, Talin A1 - Deckers, Jaap W A1 - Stritzke, Jan A1 - Lackner, Karl J A1 - Völker, Uwe A1 - Ingelsson, Erik A1 - Kullo, Iftikhar A1 - Haerting, Johannes A1 - O'Donnell, Christopher J A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - Ziegler, Andreas A1 - Reffelmann, Thorsten A1 - Redfield, Margaret M A1 - Werdan, Karl A1 - Mitchell, Gary F A1 - Rice, Kenneth A1 - Arnett, Donna K A1 - Hofman, Albert A1 - Gottdiener, John S A1 - Uitterlinden, André G A1 - Meitinger, Thomas A1 - Blettner, Maria A1 - Friedrich, Nele A1 - Wang, Thomas J A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Munzel, Thomas F A1 - Kroemer, Heyo K A1 - Benjamin, Emelia J A1 - Rotter, Jerome I A1 - Witteman, Jacqueline C A1 - Schunkert, Heribert A1 - Schmidt, Helena A1 - Völzke, Henry A1 - Blankenberg, Stefan KW - Adult KW - Aged KW - Aged, 80 and over KW - Aorta KW - Cardiovascular Diseases KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart Atria KW - Heart Ventricles KW - Humans KW - Male KW - Middle Aged KW - Organ Size KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Ventricular Dysfunction, Left KW - Ventricular Function, Left AB -

CONTEXT: 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.

VL - 302 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19584346?dopt=Abstract ER - TY - JOUR T1 - Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. JF - Circulation Y1 - 2009 A1 - Kao, W H Linda A1 - Arking, Dan E A1 - Post, Wendy A1 - Rea, Thomas D A1 - Sotoodehnia, Nona A1 - Prineas, Ronald J A1 - Bishe, Bryan A1 - Doan, Betty Q A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Coresh, Josef A1 - Siscovick, David S A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Burke, Gregory L A1 - Chakravarti, Aravinda KW - Adaptor Proteins, Signal Transducing KW - Aged KW - Death, Sudden, Cardiac KW - Electrocardiography KW - European Continental Ancestry Group KW - Genotype KW - Humans KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: 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.

VL - 119 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19204306?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of cardiovascular risk factors: design, conduct and interpretation. JF - J Thromb Haemost Y1 - 2009 A1 - Bis, J C A1 - Glazer, N L A1 - Psaty, B M KW - Cardiovascular Diseases KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Quantitative Trait Loci KW - Risk Factors AB -

Relying 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.

VL - 7 Suppl 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19630823?dopt=Abstract ER - TY - JOUR T1 - Genomewide association studies of stroke. JF - N Engl J Med Y1 - 2009 A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - DeStefano, Anita L A1 - Aulchenko, Yurii S A1 - Debette, Stephanie A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - van den Herik, Evita G A1 - Bos, Michiel J A1 - Beiser, Alexa A1 - Cushman, Mary A1 - Launer, Lenore J A1 - Shahar, Eyal A1 - Struchalin, Maksim A1 - Du, Yangchun A1 - Glazer, Nicole L A1 - Rosamond, Wayne D A1 - Rivadeneira, Fernando A1 - Kelly-Hayes, Margaret A1 - Lopez, Oscar L A1 - Coresh, Josef A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Heckbert, Susan R A1 - Koudstaal, Peter J A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Kase, Carlos S A1 - Rice, Kenneth A1 - Haritunians, Talin A1 - Roks, Gerwin A1 - de Kort, Paul L M A1 - Taylor, Kent D A1 - de Lau, Lonneke M A1 - Oostra, Ben A A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B A1 - Longstreth, W T A1 - Wolf, Philip A KW - African Continental Ancestry Group KW - Aged KW - Chromosomes, Human, Pair 12 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors KW - Stroke AB -

BACKGROUND: 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.

VL - 360 IS - 17 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of blood pressure and hypertension. JF - Nat Genet Y1 - 2009 A1 - Levy, Daniel A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Verwoert, Germaine C A1 - Launer, Lenore J A1 - Dehghan, Abbas A1 - Glazer, Nicole L A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - Aspelund, Thor A1 - Aulchenko, Yurii A1 - Lumley, Thomas A1 - Köttgen, Anna A1 - Vasan, Ramachandran S A1 - Rivadeneira, Fernando A1 - Eiriksdottir, Gudny A1 - Guo, Xiuqing A1 - Arking, Dan E A1 - Mitchell, Gary F A1 - Mattace-Raso, Francesco U S A1 - Smith, Albert V A1 - Taylor, Kent A1 - Scharpf, Robert B A1 - Hwang, Shih-Jen A1 - Sijbrands, Eric J G A1 - Bis, Joshua A1 - Harris, Tamara B A1 - Ganesh, Santhi K A1 - O'Donnell, Christopher J A1 - Hofman, Albert A1 - Rotter, Jerome I A1 - Coresh, Josef A1 - Benjamin, Emelia J A1 - Uitterlinden, André G A1 - Heiss, Gerardo A1 - Fox, Caroline S A1 - Witteman, Jacqueline C M A1 - Boerwinkle, Eric A1 - Wang, Thomas J A1 - Gudnason, Vilmundur A1 - Larson, Martin G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M KW - Blood Pressure KW - Cell Line KW - Chromosome Mapping KW - Chromosomes, Human KW - Diastole KW - Gene Expression Regulation KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Liver KW - Lymphocytes KW - Meta-Analysis as Topic KW - Odds Ratio KW - Phenotype KW - Prevalence KW - Risk Assessment KW - Systole AB -

Blood 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.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430479?dopt=Abstract ER - TY - JOUR T1 - Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease. JF - J Clin Endocrinol Metab Y1 - 2009 A1 - Patel, Shrita M A1 - Ratcliffe, Sarah J A1 - Reilly, Muredach P A1 - Weinstein, Rachel A1 - Bhasin, Shalender A1 - Blackman, Marc R A1 - Cauley, Jane A A1 - Sutton-Tyrrell, Kim A1 - Robbins, John A1 - Fried, Linda P A1 - Cappola, Anne R KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Cardiovascular Diseases KW - Coronary Disease KW - Female KW - Humans KW - Insulin KW - Insulin Resistance KW - Metabolic Syndrome KW - Odds Ratio KW - Radioimmunoassay KW - Socioeconomic Factors KW - Testosterone KW - Treatment Outcome AB -

CONTEXT: 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.

VL - 94 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19846742?dopt=Abstract ER - TY - JOUR T1 - Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. JF - Exp Gerontol Y1 - 2009 A1 - Walston, Jeremy D A1 - Matteini, Amy M A1 - Nievergelt, Caroline A1 - Lange, Leslie A A1 - Fallin, Dani M A1 - Barzilai, Nir A1 - Ziv, Elad A1 - Pawlikowska, Ludmila A1 - Kwok, Pui A1 - Cummings, Steve R A1 - Kooperberg, Charles A1 - LaCroix, Andrea A1 - Tracy, Russell P A1 - Atzmon, Gil A1 - Lange, Ethan M A1 - Reiner, Alex P KW - Aged KW - Aged, 80 and over KW - Aging KW - Cardiovascular Diseases KW - Case-Control Studies KW - Female KW - Genetic Variation KW - Genotype KW - Humans KW - Inflammation KW - Interleukin-6 KW - Longevity KW - Male KW - Phenotype KW - Poly (ADP-Ribose) Polymerase-1 KW - Poly(ADP-ribose) Polymerases KW - Risk Factors AB -

Interleukin-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.

VL - 44 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19249341?dopt=Abstract ER - TY - JOUR T1 - Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. JF - Sleep Y1 - 2009 A1 - Phillips, Barbara A1 - Bůzková, Petra A1 - Enright, Paul KW - African Americans KW - Aged KW - Cohort Studies KW - Comorbidity KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Humans KW - Hypertension KW - Male KW - Prospective Studies KW - Risk Factors KW - Sleep Initiation and Maintenance Disorders KW - United States AB -

STUDY 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.

VL - 32 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19189780?dopt=Abstract ER - TY - JOUR T1 - Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2009 A1 - Kaplan, Robert C A1 - Fitzpatrick, Annette L A1 - Pollak, Michael N A1 - Gardner, Jeffrey P A1 - Jenny, Nancy S A1 - McGinn, Aileen P A1 - Kuller, Lewis H A1 - Strickler, Howard D A1 - Kimura, Masayuki A1 - Psaty, Bruce M A1 - Aviv, Abraham KW - Aged KW - Aging KW - Cross-Sectional Studies KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor Binding Proteins KW - Insulin-Like Growth Factor I KW - Leukocytes KW - Linear Models KW - Male KW - Sex Characteristics KW - Telomere AB -

The 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.

VL - 64 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19349587?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JF - JAMA Y1 - 2009 A1 - Erqou, Sebhat A1 - Kaptoge, Stephen A1 - Perry, Philip L A1 - Di Angelantonio, Emanuele A1 - Thompson, Alexander A1 - White, Ian R A1 - Marcovina, Santica M A1 - Collins, Rory A1 - Thompson, Simon G A1 - Danesh, John KW - Cause of Death KW - Coronary Disease KW - Humans KW - Lipoprotein(a) KW - Risk Factors KW - Stroke AB -

CONTEXT: 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.

VL - 302 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19622820?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study. JF - Circ Heart Fail Y1 - 2009 A1 - Suzuki, Takeki A1 - Solomon, Cam A1 - Jenny, Nancy Swords A1 - Tracy, Russell A1 - Nelson, Jeanenne J A1 - Psaty, Bruce M A1 - Furberg, Curt A1 - Cushman, Mary KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Female KW - Fibrinogen KW - Heart Failure KW - Humans KW - Incidence KW - Inflammation Mediators KW - Interleukin-6 KW - Kaplan-Meier Estimate KW - Male KW - Population Surveillance KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

BACKGROUND: 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.

VL - 2 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19808373?dopt=Abstract ER - TY - JOUR T1 - Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology. JF - J Thromb Haemost Y1 - 2009 A1 - Steffen, L M A1 - Cushman, M A1 - Peacock, J M A1 - Heckbert, S R A1 - Jacobs, D R A1 - Rosamond, W D A1 - Folsom, A R KW - Blood Coagulation Factors KW - Blood Glucose KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Female KW - Fibrinogen KW - Humans KW - Lipids KW - Longitudinal Studies KW - Male KW - Metabolic Syndrome KW - Proportional Hazards Models KW - Risk Factors KW - Venous Thromboembolism AB -

SUMMARY 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.

VL - 7 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19175496?dopt=Abstract ER - TY - JOUR T1 - Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. JF - PLoS One Y1 - 2009 A1 - Arking, Dan E A1 - Khera, Amit A1 - Xing, Chao A1 - Kao, W H Linda A1 - Post, Wendy A1 - Boerwinkle, Eric A1 - Chakravarti, Aravinda KW - Adaptor Proteins, Signal Transducing KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Heart Diseases KW - Heart Rate KW - Hispanic Americans KW - Humans KW - Linear Models KW - Linkage Disequilibrium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sex Factors KW - Young Adult AB -

Extremes 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.

VL - 4 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19180230?dopt=Abstract ER - TY - JOUR T1 - Multiple loci associated with indices of renal function and chronic kidney disease. JF - Nat Genet Y1 - 2009 A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Katz, Ronit A1 - Li, Man A1 - Yang, Qiong A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Arking, Dan E A1 - Astor, Brad C A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Ruczinski, Ingo A1 - Scharpf, Robert B A1 - Chen, Yii-Der Ida A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Sarnak, Mark A1 - Siscovick, David A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Upadhyay, Ashish A1 - Aulchenko, Yurii S A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Chasman, Daniel I A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Fox, Caroline S KW - Chromosome Mapping KW - Cohort Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Meta-Analysis as Topic KW - Mucoproteins KW - Netherlands KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Uromodulin AB -

Chronic 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.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract ER - TY - JOUR T1 - Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. JF - Nat Genet Y1 - 2009 A1 - Ganesh, Santhi K A1 - Zakai, Neil A A1 - van Rooij, Frank J A A1 - Soranzo, Nicole A1 - Smith, Albert V A1 - Nalls, Michael A A1 - Chen, Ming-Huei A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Kuhnel, Brigitte A1 - Aspelund, Thor A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Jaffe, Andrew A1 - Bis, Joshua C M A1 - Verwoert, Germaine C A1 - Teumer, Alexander A1 - Fox, Caroline S A1 - Guralnik, Jack M A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Felix, Janine F A1 - Rendon, Augusto A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Patel, Kushang V A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Sambrook, Jennifer G A1 - Hernandez, Dena G A1 - Zheng, Gang A1 - Bandinelli, Stefania A1 - Singleton, Andrew B A1 - Coresh, Josef A1 - Lumley, Thomas A1 - Uitterlinden, André G A1 - Vangils, Janine M A1 - Launer, Lenore J A1 - Cupples, L Adrienne A1 - Oostra, Ben A A1 - Zwaginga, Jaap-Jan A1 - Ouwehand, Willem H A1 - Thein, Swee-Lay A1 - Meisinger, Christa A1 - Deloukas, Panos A1 - Nauck, Matthias A1 - Spector, Tim D A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Chakravarti, Aravinda A1 - Greinacher, Andreas A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Furth, Susan A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Lin, Jing-Ping KW - Blood Pressure KW - Cell Line KW - Cohort Studies KW - Endothelial Cells KW - Erythrocytes KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Measurements 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.

VL - 41 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract ER - TY - JOUR T1 - NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. JF - PLoS Genet Y1 - 2009 A1 - Heard-Costa, Nancy L A1 - Zillikens, M Carola A1 - Monda, Keri L A1 - Johansson, Asa A1 - Harris, Tamara B A1 - Fu, Mao A1 - Haritunians, Talin A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Garcia, Melissa A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Mitchell, Braxton D A1 - McArdle, Patrick F A1 - Shuldiner, Alan R A1 - Bielinski, Suzette J A1 - Boerwinkle, Eric A1 - Brancati, Fred A1 - Demerath, Ellen W A1 - Pankow, James S A1 - Arnold, Alice M A1 - Chen, Yii-Der Ida A1 - Glazer, Nicole L A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Amin, Najaf A1 - Campbell, Harry A1 - Gyllensten, Ulf A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Rudan, Igor A1 - Struchalin, Maksim A1 - Vitart, Veronique A1 - Gao, Xiaoyi A1 - Kraja, Aldi A1 - Province, Michael A A1 - Zhang, Qunyuan A1 - Atwood, Larry D A1 - Dupuis, Josée A1 - Hirschhorn, Joel N A1 - Jaquish, Cashell E A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - White, Charles C A1 - Aulchenko, Yurii S A1 - Estrada, Karol A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Oostra, Ben A A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - North, Kari E KW - Aged KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist Circumference AB -

Central 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.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract ER - TY - JOUR T1 - N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study. JF - Circulation Y1 - 2009 A1 - Patton, Kristen K A1 - Ellinor, Patrick T A1 - Heckbert, Susan R A1 - Christenson, Robert H A1 - DeFilippi, Christopher A1 - Gottdiener, John S A1 - Kronmal, Richard A KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Female KW - Humans KW - Immunoassay KW - Longitudinal Studies KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors AB -

BACKGROUND: 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.

VL - 120 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19841297?dopt=Abstract ER - TY - JOUR T1 - Platelet count and the risk for thrombosis and death in the elderly. JF - J Thromb Haemost Y1 - 2009 A1 - van der Bom, J G A1 - Heckbert, S R A1 - Lumley, T A1 - Holmes, C E A1 - Cushman, M A1 - Folsom, A R A1 - Rosendaal, F R A1 - Psaty, B M KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Cerebral Hemorrhage KW - Female KW - Humans KW - Male KW - Myocardial Infarction KW - Platelet Count KW - Risk KW - Stroke KW - Survival Analysis KW - Thrombosis KW - Venous Thrombosis AB -

AIM: 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.

VL - 7 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19143922?dopt=Abstract ER - TY - JOUR T1 - Prevalence of hearing loss in Black and White elders: results of the Cardiovascular Health Study. JF - J Speech Lang Hear Res Y1 - 2009 A1 - Pratt, Sheila R A1 - Kuller, Lewis A1 - Talbott, Evelyn O A1 - McHugh-Pemu, Kathleen A1 - Buhari, Alhaji M A1 - Xu, Xiaohui KW - African Americans KW - Aged KW - Aged, 80 and over KW - Aging KW - Auditory Threshold KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Hearing Loss KW - Hearing Tests KW - Humans KW - Male KW - Occupations KW - Prevalence KW - Sex Characteristics KW - Smoking KW - Socioeconomic Factors KW - United States AB -

PURPOSE: 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.

VL - 52 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19380605?dopt=Abstract ER - TY - JOUR T1 - Race, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2009 A1 - Parashar, Susmita A1 - Katz, Ronit A1 - Smith, Nicholas L A1 - Arnold, Alice M A1 - Vaccarino, Viola A1 - Wenger, Nanette K A1 - Gottdiener, John S KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Proportional Hazards Models KW - Sex Factors KW - United States AB -

In 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.

VL - 103 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19361600?dopt=Abstract ER - TY - JOUR T1 - Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis. JF - J Thromb Haemost Y1 - 2009 A1 - Smith, N L A1 - Wiggins, K L A1 - Reiner, A P A1 - Lange, L A A1 - Cushman, M A1 - Heckbert, S R A1 - Lumley, T A1 - Rice, K M A1 - Folsom, A R A1 - Psaty, B M KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Haplotypes KW - Hemostasis KW - Humans KW - Incidence KW - Male KW - Menopause KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results KW - Risk KW - Thrombophilia KW - Venous Thrombosis KW - Young Adult VL - 7 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19682239?dopt=Abstract ER - TY - JOUR T1 - Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 2009 A1 - Yanez, N David A1 - Burke, Gregory L A1 - Manolio, Teri A1 - Gardin, Julius M A1 - Polak, Joseph KW - Aged KW - Atherosclerosis KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Incidence KW - Male KW - Myocardial Infarction KW - Odds Ratio KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Siblings KW - Stroke KW - United States AB -

PURPOSE: 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.

VL - 19 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19944349?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and mortality: a prospective cohort study. JF - PLoS Med Y1 - 2009 A1 - Punjabi, Naresh M A1 - Caffo, Brian S A1 - Goodwin, James L A1 - Gottlieb, Daniel J A1 - Newman, Anne B A1 - O'Connor, George T A1 - Rapoport, David M A1 - Redline, Susan A1 - Resnick, Helaine E A1 - Robbins, John A A1 - Shahar, Eyal A1 - Unruh, Mark L A1 - Samet, Jonathan M KW - Aged KW - Coronary Artery Disease KW - Female KW - Humans KW - Hypoxia KW - Male KW - Middle Aged KW - Odds Ratio KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors KW - Sleep Apnea Syndromes KW - Survival Analysis AB -

BACKGROUND: 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.

VL - 6 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19688045?dopt=Abstract ER - TY - JOUR T1 - Systematically missing confounders in individual participant data meta-analysis of observational cohort studies. JF - Stat Med Y1 - 2009 A1 - Jackson, Dan A1 - White, Ian A1 - Kostis, J B A1 - Wilson, A C A1 - Folsom, A R A1 - Wu, K A1 - Chambless, L A1 - Benderly, M A1 - Goldbourt, U A1 - Willeit, J A1 - Kiechl, S A1 - Yarnell, J W G A1 - Sweetnam, P M A1 - Elwood, P C A1 - Cushman, M A1 - Psaty, B M A1 - Tracy, R P A1 - Tybjaerg-Hansen, A A1 - Haverkate, F A1 - de Maat, M P M A1 - Thompson, S G A1 - Fowkes, F G R A1 - Lee, A J A1 - Smith, F B A1 - Salomaa, V A1 - Harald, K A1 - Rasi, V A1 - Vahtera, E A1 - Jousilahti, P A1 - D'Agostino, R A1 - Kannel, W B A1 - Wilson, P W F A1 - Tofler, G A1 - Levy, D A1 - Marchioli, R A1 - Valagussa, F A1 - Rosengren, A A1 - Wilhelmsen, L A1 - Lappas, G A1 - Eriksson, H A1 - Cremer, P A1 - Nagel, D A1 - Curb, J D A1 - Rodriguez, B A1 - Yano, K A1 - Salonen, J T A1 - Nyyssönen, K A1 - Tuomainen, T-P A1 - Hedblad, B A1 - Engstrom, G A1 - Berglund, G A1 - Loewel, H A1 - Koenig, W A1 - Hense, H W A1 - Meade, T W A1 - Cooper, J A A1 - De Stavola, B A1 - Knottenbelt, C A1 - Miller, G J A1 - Cooper, J A A1 - Bauer, K A A1 - Rosenberg, R D A1 - Sato, S A1 - Kitamura, A A1 - Naito, Y A1 - Iso, H A1 - Salomaa, V A1 - Harald, K A1 - Rasi, V A1 - Vahtera, E A1 - Jousilahti, P A1 - Palosuo, T A1 - Ducimetiere, P A1 - Amouyel, P A1 - Arveiler, D A1 - Evans, A E A1 - Ferrieres, J A1 - Juhan-Vague, I A1 - Bingham, A A1 - Schulte, H A1 - Assmann, G A1 - Cantin, B A1 - Lamarche, B A1 - Després, J-P A1 - Dagenais, G R A1 - Tunstall-Pedoe, H A1 - Lowe, G D O A1 - Woodward, M A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Palmieri, V A1 - Yeh, J L A1 - Meade, T W A1 - Rudnicka, A A1 - Brennan, P A1 - Knottenbelt, C A1 - Cooper, J A A1 - Ridker, P A1 - Rodeghiero, F A1 - Tosetto, A A1 - Shepherd, J A1 - Lowe, G D O A1 - Ford, I A1 - Robertson, M A1 - Brunner, E A1 - Shipley, M A1 - Feskens, E J M A1 - Di Angelantonio, E A1 - Kaptoge, S A1 - Lewington, S A1 - Lowe, G D O A1 - Sarwar, N A1 - Thompson, S G A1 - Walker, M A1 - Watson, S A1 - White, I R A1 - Wood, A M A1 - Danesh, J KW - Cohort Studies KW - Computer Simulation KW - Coronary Disease KW - Data Interpretation, Statistical KW - Female KW - Fibrinogen KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Models, Statistical AB -

One 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

VL - 28 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19222087?dopt=Abstract ER - TY - JOUR T1 - Total and cause-specific mortality in the cardiovascular health study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2009 A1 - Newman, Anne B A1 - Sachs, Michael C A1 - Arnold, Alice M A1 - Fried, Linda P A1 - Kronmal, Richard A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Harris, Tamara B A1 - Robbins, John A A1 - Burke, Gregory L A1 - Kuller, Lewis H A1 - Lumley, Thomas KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Cardiovascular Diseases KW - Cause of Death KW - Chronic Disease KW - Cohort Studies KW - Female KW - Geriatric Assessment KW - Health Surveys KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Probability KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Assessment KW - Severity of Illness Index KW - Sex Factors KW - Survival Analysis KW - United States AB -

BACKGROUND: 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.

VL - 64 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19723772?dopt=Abstract ER - TY - JOUR T1 - Usefulness of myeloperoxidase levels in healthy elderly subjects to predict risk of developing heart failure. JF - Am J Cardiol Y1 - 2009 A1 - Tang, W H Wilson A1 - Katz, Ronit A1 - Brennan, Marie-Luise A1 - Aviles, Ronnier J A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Hazen, Stanley L KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Disease Progression KW - Female KW - Geriatric Assessment KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Male KW - Peroxidase KW - Predictive Value of Tests KW - Probability KW - Prognosis KW - Risk Assessment KW - Sensitivity and Specificity KW - Severity of Illness Index KW - Sex Factors AB -

Increased 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 ( VL - 103 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19406270?dopt=Abstract ER - TY - JOUR T1 - Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. JF - Nat Genet Y1 - 2009 A1 - Benjamin, Emelia J A1 - Rice, Kenneth M A1 - Arking, Dan E A1 - Pfeufer, Arne A1 - van Noord, Charlotte A1 - Smith, Albert V A1 - Schnabel, Renate B A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Sinner, Moritz F A1 - Dehghan, Abbas A1 - Lubitz, Steven A A1 - D'Agostino, Ralph B A1 - Lumley, Thomas A1 - Ehret, Georg B A1 - Heeringa, Jan A1 - Aspelund, Thor A1 - Newton-Cheh, Christopher A1 - Larson, Martin G A1 - Marciante, Kristin D A1 - Soliman, Elsayed Z A1 - Rivadeneira, Fernando A1 - Wang, Thomas J A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Psaty, Bruce M A1 - Li, Man A1 - Chamberlain, Alanna M A1 - Hofman, Albert A1 - Vasan, Ramachandran S A1 - Harris, Tamara B A1 - Rotter, Jerome I A1 - Kao, W H Linda A1 - Agarwal, Sunil K A1 - Stricker, Bruno H Ch A1 - Wang, Ke A1 - Launer, Lenore J A1 - Smith, Nicholas L A1 - Chakravarti, Aravinda A1 - Uitterlinden, André G A1 - Wolf, Philip A A1 - Sotoodehnia, Nona A1 - Köttgen, Anna A1 - van Duijn, Cornelia M A1 - Meitinger, Thomas A1 - Mueller, Martina A1 - Perz, Siegfried A1 - Steinbeck, Gerhard A1 - Wichmann, H-Erich A1 - Lunetta, Kathryn L A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Witteman, Jacqueline C M KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 16 KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeodomain Proteins KW - Humans KW - Meta-Analysis as Topic KW - Mutation KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results AB -

We 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)).

VL - 41 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract ER - TY - JOUR T1 - Admixture mapping of ankle-arm index: identification of a candidate locus associated with peripheral arterial disease. JF - J Med Genet Y1 - 2010 A1 - Scherer, M L A1 - Nalls, M A A1 - Pawlikowska, L A1 - Ziv, E A1 - Mitchell, G A1 - Huntsman, S A1 - Hu, D A1 - Sutton-Tyrrell, K A1 - Lakatta, E G A1 - Hsueh, W-C A1 - Newman, A B A1 - Tandon, A A1 - Kim, L A1 - Kwok, P-Y A1 - Sung, A A1 - Li, R A1 - Psaty, B A1 - Reiner, A P A1 - Harris, T KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Chromosome Mapping KW - Chromosomes, Human, Pair 11 KW - Female KW - Genetic Loci KW - Genotype KW - Humans KW - Male KW - Odds Ratio KW - Peripheral Vascular Diseases KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 47 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19586928?dopt=Abstract ER - TY - JOUR T1 - Albuminuria and the risk of incident stroke and stroke types in older adults. JF - Neurology Y1 - 2010 A1 - Aguilar, M I A1 - O'Meara, E S A1 - Seliger, S A1 - Longstreth, W T A1 - Hart, R G A1 - Pergola, P E A1 - Shlipak, M G A1 - Katz, R A1 - Sarnak, M J A1 - Rifkin, D E KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Community Health Services KW - Confidence Intervals KW - Female KW - Geriatric Assessment KW - Glomerular Filtration Rate KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Factors KW - Stroke AB -

BACKGROUND: 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.

VL - 75 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20810996?dopt=Abstract ER - TY - JOUR T1 - Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. JF - Nat Genet Y1 - 2010 A1 - Speliotes, Elizabeth K A1 - Willer, Cristen J A1 - Berndt, Sonja I A1 - Monda, Keri L A1 - Thorleifsson, Gudmar A1 - Jackson, Anne U A1 - Lango Allen, Hana A1 - Lindgren, Cecilia M A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Workalemahu, Tsegaselassie A1 - Heid, Iris M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Weedon, Michael N A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Ferreira, Teresa A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Estrada, Karol A1 - Liang, Liming A1 - Nemesh, James A1 - Park, Ju-Hyun A1 - Gustafsson, Stefan A1 - Kilpeläinen, Tuomas O A1 - Yang, Jian A1 - Bouatia-Naji, Nabila A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Raychaudhuri, Soumya A1 - Scherag, Andre A1 - Smith, Albert Vernon A1 - Welch, Ryan A1 - Zhao, Jing Hua A1 - Aben, Katja K A1 - Absher, Devin M A1 - Amin, Najaf A1 - Dixon, Anna L A1 - Fisher, Eva A1 - Glazer, Nicole L A1 - Goddard, Michael E A1 - Heard-Costa, Nancy L A1 - Hoesel, Volker A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Lamina, Claudia A1 - Li, Shengxu A1 - Moffatt, Miriam F A1 - Myers, Richard H A1 - Narisu, Narisu A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan P A1 - van Wingerden, Sophie A1 - Watanabe, Richard M A1 - White, Charles C A1 - Wiklund, Fredrik A1 - Barlassina, Christina A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Prokopenko, Inga A1 - Shi, Jianxin A1 - Thiering, Elisabeth A1 - Alavere, Helene A1 - Alibrandi, Maria T S A1 - Almgren, Peter A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Atwood, Larry D A1 - Balkau, Beverley A1 - Balmforth, Anthony J A1 - Bennett, Amanda J A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Biebermann, Heike A1 - Blakemore, Alexandra I F A1 - Boes, Tanja A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Brown, Morris J A1 - Buchanan, Thomas A A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Cavalcanti-Proença, Christine A1 - Chen, Yii-Der Ida A1 - Chen, Chih-Mei A1 - Chines, Peter S A1 - Clarke, Robert A1 - Coin, Lachlan A1 - Connell, John A1 - Day, Ian N M A1 - den Heijer, Martin A1 - Duan, Jubao A1 - Ebrahim, Shah A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eiriksdottir, Gudny A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Facheris, Maurizio F A1 - Felix, Stephan B A1 - Fischer-Posovszky, Pamela A1 - Folsom, Aaron R A1 - Friedrich, Nele A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Gejman, Pablo V A1 - Geus, Eco J C A1 - Gieger, Christian A1 - Gjesing, Anette P A1 - Goel, Anuj A1 - Goyette, Philippe A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Greenawalt, Danielle M A1 - Groves, Christopher J A1 - Gudnason, Vilmundur A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hall, Alistair S A1 - Havulinna, Aki S A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hinney, Anke A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jacobs, Kevin B A1 - Jarick, Ivonne A1 - Jewell, Elizabeth A1 - John, Ulrich A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kajantie, Eero A1 - Kaplan, Lee M A1 - Kathiresan, Sekar A1 - Kettunen, Johannes A1 - Kinnunen, Leena A1 - Knowles, Joshua W A1 - Kolcic, Ivana A1 - König, Inke R A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kuusisto, Johanna A1 - Kraft, Peter A1 - Kvaløy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lanzani, Chiara A1 - Launer, Lenore J A1 - Lecoeur, Cécile A1 - Lehtimäki, Terho A1 - Lettre, Guillaume A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - Manunta, Paolo A1 - Marek, Diana A1 - Marre, Michel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - McKnight, Barbara A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Meyre, David A1 - Midthjell, Kristian A1 - Montgomery, Grant W A1 - Morken, Mario A A1 - Morris, Andrew P A1 - Mulic, Rosanda A1 - Ngwa, Julius S A1 - Nelis, Mari A1 - Neville, Matt J A1 - Nyholt, Dale R A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Ong, Ken K A1 - Oostra, Ben A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Perola, Markus A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Rafelt, Suzanne A1 - Raitakari, Olli A1 - Rayner, Nigel W A1 - Ridderstråle, Martin A1 - Rief, Winfried A1 - Ruokonen, Aimo A1 - Robertson, Neil R A1 - Rzehak, Peter A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sandhu, Manjinder S A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Savolainen, Markku J A1 - Scherag, Susann A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Silander, Kaisa A1 - Sinisalo, Juha A1 - Siscovick, David S A1 - Smit, Jan H A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Stephens, Jonathan A1 - Surakka, Ida A1 - Swift, Amy J A1 - Tammesoo, Mari-Liis A1 - Tardif, Jean-Claude A1 - Teder-Laving, Maris A1 - Teslovich, Tanya M A1 - Thompson, John R A1 - Thomson, Brian A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Viikari, Jorma A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogel, Carla I G A1 - Voight, Benjamin F A1 - Waite, Lindsay L A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wiegand, Susanna A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Witteman, Jacqueline C A1 - Xu, Jianfeng A1 - Zhang, Qunyuan A1 - Zgaga, Lina A1 - Ziegler, Andreas A1 - Zitting, Paavo A1 - Beilby, John P A1 - Farooqi, I Sadaf A1 - Hebebrand, Johannes A1 - Huikuri, Heikki V A1 - James, Alan L A1 - Kähönen, Mika A1 - Levinson, Douglas F A1 - Macciardi, Fabio A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Beckmann, Jacques S A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Collins, Francis S A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Erdmann, Jeanette A1 - Froguel, Philippe A1 - Grönberg, Henrik A1 - Gyllensten, Ulf A1 - Hall, Per A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayes, Richard B A1 - Heinrich, Joachim A1 - Hu, Frank B A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Kaprio, Jaakko A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Kiemeney, Lambertus A A1 - Krude, Heiko A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Metspalu, Andres A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Pedersen, Oluf A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Reinehr, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Spector, Timothy D A1 - Tuomilehto, Jaakko A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Valle, Timo T A1 - Wabitsch, Martin A1 - Waeber, Gérard A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Chatterjee, Nilanjan A1 - McCarroll, Steven A A1 - Purcell, Shaun A1 - Schadt, Eric E A1 - Visscher, Peter M A1 - Assimes, Themistocles L A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Frayling, Timothy M A1 - Thorsteinsdottir, Unnur A1 - Abecasis, Goncalo R A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Stefansson, Kari A1 - North, Kari E A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Ingelsson, Erik A1 - Loos, Ruth J F KW - Body Height KW - Body Mass Index KW - Body Size KW - Body Weight KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity 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.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract ER - TY - JOUR T1 - Association 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. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Smith, Nicholas L A1 - Felix, Janine F A1 - Morrison, Alanna C A1 - Demissie, Serkalem A1 - Glazer, Nicole L A1 - Loehr, Laura R A1 - Cupples, L Adrienne A1 - Dehghan, Abbas A1 - Lumley, Thomas A1 - Rosamond, Wayne D A1 - Lieb, Wolfgang A1 - Rivadeneira, Fernando A1 - Bis, Joshua C A1 - Folsom, Aaron R A1 - Benjamin, Emelia A1 - Aulchenko, Yurii S A1 - Haritunians, Talin A1 - Couper, David A1 - Murabito, Joanne A1 - Wang, Ying A A1 - Stricker, Bruno H A1 - Gottdiener, John S A1 - Chang, Patricia P A1 - Wang, Thomas J A1 - Rice, Kenneth M A1 - Hofman, Albert A1 - Heckbert, Susan R A1 - Fox, Ervin R A1 - O'Donnell, Christopher J A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Willerson, James T A1 - Levy, Daniel A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Witteman, Jacqueline C M A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Endopeptidases KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk KW - Ubiquitin-Specific Proteases AB -

BACKGROUND: 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.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20445134?dopt=Abstract ER - TY - JOUR T1 - Associations between renal duplex parameters and adverse cardiovascular events in the elderly: a prospective cohort study. JF - Am J Kidney Dis Y1 - 2010 A1 - Pearce, Jeffrey D A1 - Craven, Timothy E A1 - Edwards, Matthew S A1 - Corriere, Matthew A A1 - Crutchley, Teresa A A1 - Fleming, Shawn H A1 - Hansen, Kimberley J KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Kidney Diseases KW - Male KW - Renal Artery KW - Risk Factors KW - Ultrasonography, Doppler, Duplex AB -

BACKGROUND: 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.

VL - 55 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20116688?dopt=Abstract ER - TY - JOUR T1 - Associations of PM10 with sleep and sleep-disordered breathing in adults from seven U.S. urban areas. JF - Am J Respir Crit Care Med Y1 - 2010 A1 - Zanobetti, Antonella A1 - Redline, Susan A1 - Schwartz, Joel A1 - Rosen, Dennis A1 - Patel, Sanjay A1 - O'Connor, George T A1 - Lebowitz, Michael A1 - Coull, Brent A A1 - Gold, Diane R KW - Adult KW - Aged KW - Aged, 80 and over KW - Air Pollutants KW - Air Pollution KW - Cities KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Multicenter Studies as Topic KW - Particle Size KW - Particulate Matter KW - Polysomnography KW - Seasons KW - Severity of Illness Index KW - Sleep KW - Sleep Apnea Syndromes KW - Temperature KW - United States KW - Urban Health AB -

RATIONALE: 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.

VL - 182 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20508218?dopt=Abstract ER - TY - JOUR T1 - Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables. JF - Stat Med Y1 - 2010 A1 - Burgess, Stephen A1 - Thompson, Simon G A1 - Burgess, S A1 - Thompson, S G A1 - Andrews, G A1 - Samani, N J A1 - Hall, A A1 - Whincup, P A1 - Morris, R A1 - Lawlor, D A A1 - Davey Smith, G A1 - Timpson, N A1 - Ebrahim, S A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Timpson, N A1 - Brown, M A1 - Ricketts, S A1 - Sandhu, M A1 - Reiner, A A1 - Psaty, B A1 - Lange, L A1 - Cushman, M A1 - Hung, J A1 - Thompson, P A1 - Beilby, J A1 - Warrington, N A1 - Palmer, L J A1 - Nordestgaard, B G A1 - Tybjaerg-Hansen, A A1 - Zacho, J A1 - Wu, C A1 - Lowe, G A1 - Tzoulaki, I A1 - Kumari, M A1 - Sandhu, M A1 - Yamamoto, J F A1 - Chiodini, B A1 - Franzosi, M A1 - Hankey, G J A1 - Jamrozik, K A1 - Palmer, L A1 - Rimm, E A1 - Pai, J A1 - Psaty, B A1 - Heckbert, S A1 - Bis, J A1 - Anand, S A1 - Engert, J A1 - Collins, R A1 - Clarke, R A1 - Melander, O A1 - Berglund, G A1 - Ladenvall, P A1 - Johansson, L A1 - Jansson, J-H A1 - Hallmans, G A1 - Hingorani, A A1 - Humphries, S A1 - Rimm, E A1 - Manson, J A1 - Pai, J A1 - Watkins, H A1 - Clarke, R A1 - Hopewell, J A1 - Saleheen, D A1 - Frossard, R A1 - Danesh, J A1 - Sattar, N A1 - Robertson, M A1 - Shepherd, J A1 - Schaefer, E A1 - Hofman, A A1 - Witteman, J C M A1 - Kardys, I A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Timpson, N A1 - de Faire, U A1 - Bennet, A A1 - Sattar, N A1 - Ford, I A1 - Packard, C A1 - Kumari, M A1 - Manson, J A1 - Lawlor, Debbie A A1 - Davey Smith, George A1 - Anand, S A1 - Collins, R A1 - Casas, J P A1 - Danesh, J A1 - Davey Smith, G A1 - Franzosi, M A1 - Hingorani, A A1 - Lawlor, D A A1 - Manson, J A1 - Nordestgaard, B G A1 - Samani, N J A1 - Sandhu, M A1 - Smeeth, L A1 - Wensley, F A1 - Anand, S A1 - Bowden, J A1 - Burgess, S A1 - Casas, J P A1 - Di Angelantonio, E A1 - Engert, J A1 - Gao, P A1 - Shah, T A1 - Smeeth, L A1 - Thompson, S G A1 - Verzilli, C A1 - Walker, M A1 - Whittaker, J A1 - Hingorani, A A1 - Danesh, J KW - Bayes Theorem KW - Biostatistics KW - C-Reactive Protein KW - Fibrinogen KW - Genetic Markers KW - Humans KW - Meta-Analysis as Topic KW - Models, Statistical KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Genetic 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.

VL - 29 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20209660?dopt=Abstract ER - TY - JOUR T1 - Biological, clinical and population relevance of 95 loci for blood lipids. JF - Nature Y1 - 2010 A1 - Teslovich, Tanya M A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Ripatti, Samuli A1 - Chasman, Daniel I A1 - Willer, Cristen J A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Isaacs, Aaron A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - Feitosa, Mary F A1 - Chambers, John A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Johnson, Toby A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Li, Mingyao A1 - Shin Cho, Yoon A1 - Jin Go, Min A1 - Jin Kim, Young A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Twee-Hee Ong, Rick A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Song, Kijoung A1 - Hua Zhao, Jing A1 - Yuan, Xin A1 - Luan, Jian'an A1 - Lamina, Claudia A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Wright, Alan F A1 - Witteman, Jacqueline C M A1 - Wilson, James F A1 - Willemsen, Gonneke A1 - Wichmann, H-Erich A1 - Whitfield, John B A1 - Waterworth, Dawn M A1 - Wareham, Nicholas J A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Voight, Benjamin F A1 - Vitart, Veronique A1 - Uitterlinden, André G A1 - Uda, Manuela A1 - Tuomilehto, Jaakko A1 - Thompson, John R A1 - Tanaka, Toshiko A1 - Surakka, Ida A1 - Stringham, Heather M A1 - Spector, Tim D A1 - Soranzo, Nicole A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Silander, Kaisa A1 - Sijbrands, Eric J G A1 - Scuteri, Angelo A1 - Scott, James A1 - Schlessinger, David A1 - Sanna, Serena A1 - Salomaa, Veikko A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Ruokonen, Aimo A1 - Rudan, Igor A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Psaty, Bruce M A1 - Pramstaller, Peter P A1 - Pichler, Irene A1 - Perola, Markus A1 - Penninx, Brenda W J H A1 - Pedersen, Nancy L A1 - Pattaro, Cristian A1 - Parker, Alex N A1 - Paré, Guillaume A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - Meitinger, Thomas A1 - McPherson, Ruth A1 - McCarthy, Mark I A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Mangino, Massimo A1 - Magnusson, Patrik K E A1 - Lucas, Gavin A1 - Luben, Robert A1 - Loos, Ruth J F A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - Kronenberg, Florian A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaprio, Jaakko A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Jarvelin, Marjo-Riitta A1 - Janssens, A Cecile J W A1 - Ingelsson, Erik A1 - Igl, Wilmar A1 - Kees Hovingh, G A1 - Hottenga, Jouke-Jan A1 - Hofman, Albert A1 - Hicks, Andrew A A1 - Hengstenberg, Christian A1 - Heid, Iris M A1 - Hayward, Caroline A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Gyllensten, Ulf A1 - Guiducci, Candace A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Gieger, Christian A1 - Freimer, Nelson B A1 - Ferrucci, Luigi A1 - Erdmann, Jeanette A1 - Elliott, Paul A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Geus, Eco J C A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Collins, Francis S A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Campbell, Harry A1 - Burtt, Noel P A1 - Bonnycastle, Lori L A1 - Boomsma, Dorret I A1 - Boekholdt, S Matthijs A1 - Bergman, Richard N A1 - Barroso, Inês A1 - Bandinelli, Stefania A1 - Ballantyne, Christie M A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Altshuler, David A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Adair, Linda S A1 - Taylor, Herman A A1 - Borecki, Ingrid B A1 - Gabriel, Stacey B A1 - Wilson, James G A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Mohlke, Karen L A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Strachan, David P A1 - Mooser, Vincent A1 - Stefansson, Kari A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Kathiresan, Sekar KW - African Americans KW - Animals KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Male KW - Mice KW - N-Acetylgalactosaminyltransferases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Protein Phosphatase 1 KW - Reproducibility of Results KW - Triglycerides AB -

Plasma 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.

VL - 466 IS - 7307 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract ER - TY - JOUR T1 - Brain structure and obesity. JF - Hum Brain Mapp Y1 - 2010 A1 - Raji, Cyrus A A1 - Ho, April J A1 - Parikshak, Neelroop N A1 - Becker, James T A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Hua, Xue A1 - Leow, Alex D A1 - Toga, Arthur W A1 - Thompson, Paul M KW - Age Factors KW - Aged KW - Analysis of Variance KW - Body Mass Index KW - Brain KW - Continental Population Groups KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Humans KW - Insulin KW - Magnetic Resonance Imaging KW - Male KW - Nerve Fibers, Myelinated KW - Nerve Fibers, Unmyelinated KW - Obesity KW - Organ Size KW - Regression Analysis KW - Sex Factors AB -

Obesity 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.

VL - 31 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19662657?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association resource (CARe): design, methods, and proof of concept. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Musunuru, Kiran A1 - Lettre, Guillaume A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Pirruccello, James P A1 - Ejebe, Kenechi G A1 - Keating, Brendan J A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Lapchyk, Nina A1 - Crenshaw, Andrew A1 - Ziaugra, Liuda A1 - Rachupka, Anthony A1 - Benjamin, Emelia J A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Hirschhorn, Joel N A1 - Newton-Cheh, Christopher A1 - Nizzari, Marcia M A1 - Paltoo, Dina N A1 - Papanicolaou, George J A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Kathiresan, Sekar A1 - Fabsitz, Richard R A1 - Boerwinkle, Eric A1 - Gabriel, Stacey B KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Databases, Genetic KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genotype KW - Humans KW - Phenotype KW - Pilot Projects KW - Polymorphism, Single Nucleotide KW - Research Design KW - Triglycerides AB -

BACKGROUND: 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.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract ER - TY - JOUR T1 - Chronic medical conditions and the sex-based disparity in disability: the Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Whitson, Heather E A1 - Landerman, Lawrence R A1 - Newman, Anne B A1 - Fried, Linda P A1 - Pieper, Carl F A1 - Cohen, Harvey Jay KW - Aged KW - Arthritis KW - Cardiovascular Diseases KW - Chronic Disease KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Disabled Persons KW - Emphysema KW - Female KW - Hearing Disorders KW - Humans KW - Male KW - Obesity KW - Prevalence KW - Sex Distribution AB -

BACKGROUND: 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.

VL - 65 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20675619?dopt=Abstract ER - TY - JOUR T1 - Combined association of lipids and blood pressure in relation to incident cardiovascular disease in the elderly: the cardiovascular health study. JF - Am J Hypertens Y1 - 2010 A1 - Wong, Nathan D A1 - Lopez, Victor A A1 - Roberts, Craig S A1 - Solomon, Henry A A1 - Burke, Gregory L A1 - Kuller, Lewis A1 - Tracy, Russell A1 - Yanez, David A1 - Psaty, Bruce M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Mellitus KW - Female KW - Health Surveys KW - Humans KW - Likelihood Functions KW - Lipids KW - Male KW - Proportional Hazards Models KW - Sex Factors KW - Smoking KW - Socioeconomic Factors KW - United States AB -

BACKGROUND: 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.

VL - 23 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19927131?dopt=Abstract ER - TY - JOUR T1 - Common genetic determinants of vitamin D insufficiency: a genome-wide association study. JF - Lancet Y1 - 2010 A1 - Wang, Thomas J A1 - Zhang, Feng A1 - Richards, J Brent A1 - Kestenbaum, Bryan A1 - van Meurs, Joyce B A1 - Berry, Diane A1 - Kiel, Douglas P A1 - Streeten, Elizabeth A A1 - Ohlsson, Claes A1 - Koller, Daniel L A1 - Peltonen, Leena A1 - Cooper, Jason D A1 - O'Reilly, Paul F A1 - Houston, Denise K A1 - Glazer, Nicole L A1 - Vandenput, Liesbeth A1 - Peacock, Munro A1 - Shi, Julia A1 - Rivadeneira, Fernando A1 - McCarthy, Mark I A1 - Anneli, Pouta A1 - de Boer, Ian H A1 - Mangino, Massimo A1 - Kato, Bernet A1 - Smyth, Deborah J A1 - Booth, Sarah L A1 - Jacques, Paul F A1 - Burke, Greg L A1 - Goodarzi, Mark A1 - Cheung, Ching-Lung A1 - Wolf, Myles A1 - Rice, Kenneth A1 - Goltzman, David A1 - Hidiroglou, Nick A1 - Ladouceur, Martin A1 - Wareham, Nicholas J A1 - Hocking, Lynne J A1 - Hart, Deborah A1 - Arden, Nigel K A1 - Cooper, Cyrus A1 - Malik, Suneil A1 - Fraser, William D A1 - Hartikainen, Anna-Liisa A1 - Zhai, Guangju A1 - Macdonald, Helen M A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Reid, David M A1 - Hakim, Alan A1 - Dennison, Elaine A1 - Liu, Yongmei A1 - Power, Chris A1 - Stevens, Helen E A1 - Jaana, Laitinen A1 - Vasan, Ramachandran S A1 - Soranzo, Nicole A1 - Bojunga, Jörg A1 - Psaty, Bruce M A1 - Lorentzon, Mattias A1 - Foroud, Tatiana A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Jansson, John-Olov A1 - Cauley, Jane A A1 - Uitterlinden, André G A1 - Gibson, Quince A1 - Jarvelin, Marjo-Riitta A1 - Karasik, David A1 - Siscovick, David S A1 - Econs, Michael J A1 - Kritchevsky, Stephen B A1 - Florez, Jose C A1 - Todd, John A A1 - Dupuis, Josée A1 - Hyppönen, Elina A1 - Spector, Timothy D KW - Canada KW - Chromosomes, Human, Pair 11 KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - Dietary Supplements KW - Europe KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoassay KW - International Cooperation KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide KW - Seasons KW - United States KW - Vitamin D KW - Vitamin D Deficiency AB -

BACKGROUND: 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).

VL - 376 IS - 9736 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20541252?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants associate with serum phosphorus concentration. JF - J Am Soc Nephrol Y1 - 2010 A1 - Kestenbaum, Bryan A1 - Glazer, Nicole L A1 - Köttgen, Anna A1 - Felix, Janine F A1 - Hwang, Shih-Jen A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Hausman, Dorothy B A1 - Petersen, Ann-Kristin A1 - Gieger, Christian A1 - Ried, Janina S A1 - Meitinger, Thomas A1 - Strom, Tim M A1 - Wichmann, H Erich A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Rudan, Igor A1 - de Boer, Ian H A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Chen, Yii-Der Ida A1 - Li, Man A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Yang, Qiong A1 - Levy, Daniel A1 - van Rooij, Frank J A A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Shlipak, Michael G A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Siscovick, David S A1 - Fox, Caroline S KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Fibroblast Growth Factors KW - Gene Frequency KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Middle Aged KW - Phosphorus KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing KW - Sex Factors KW - Sodium-Phosphate Cotransporter Proteins, Type IIa AB -

Phosphorus 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.

VL - 21 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract ER - TY - JOUR T1 - Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. JF - Nat Genet Y1 - 2010 A1 - Sotoodehnia, Nona A1 - Isaacs, Aaron A1 - de Bakker, Paul I W A1 - Dörr, Marcus A1 - Newton-Cheh, Christopher A1 - Nolte, Ilja M A1 - van der Harst, Pim A1 - Müller, Martina A1 - Eijgelsheim, Mark A1 - Alonso, Alvaro A1 - Hicks, Andrew A A1 - Padmanabhan, Sandosh A1 - Hayward, Caroline A1 - Smith, Albert Vernon A1 - Polasek, Ozren A1 - Giovannone, Steven A1 - Fu, Jingyuan A1 - Magnani, Jared W A1 - Marciante, Kristin D A1 - Pfeufer, Arne A1 - Gharib, Sina A A1 - Teumer, Alexander A1 - Li, Man A1 - Bis, Joshua C A1 - Rivadeneira, Fernando A1 - Aspelund, Thor A1 - Köttgen, Anna A1 - Johnson, Toby A1 - Rice, Kenneth A1 - Sie, Mark P S A1 - Wang, Ying A A1 - Klopp, Norman A1 - Fuchsberger, Christian A1 - Wild, Sarah H A1 - Mateo Leach, Irene A1 - Estrada, Karol A1 - Völker, Uwe A1 - Wright, Alan F A1 - Asselbergs, Folkert W A1 - Qu, Jiaxiang A1 - Chakravarti, Aravinda A1 - Sinner, Moritz F A1 - Kors, Jan A A1 - Petersmann, Astrid A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Oostra, Ben A A1 - Cupples, L Adrienne A1 - Perz, Siegfried A1 - de Boer, Rudolf A A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Spector, Timothy D A1 - Liu, Fang-Yu A1 - Boerwinkle, Eric A1 - Dominiczak, Anna F A1 - Rotter, Jerome I A1 - van Herpen, Gé A1 - Levy, Daniel A1 - Wichmann, H-Erich A1 - van Gilst, Wiek H A1 - Witteman, Jacqueline C M A1 - Kroemer, Heyo K A1 - Kao, W H Linda A1 - Heckbert, Susan R A1 - Meitinger, Thomas A1 - Hofman, Albert A1 - Campbell, Harry A1 - Folsom, Aaron R A1 - van Veldhuisen, Dirk J A1 - Schwienbacher, Christine A1 - O'Donnell, Christopher J A1 - Volpato, Claudia Beu A1 - Caulfield, Mark J A1 - Connell, John M A1 - Launer, Lenore A1 - Lu, Xiaowen A1 - Franke, Lude A1 - Fehrmann, Rudolf S N A1 - te Meerman, Gerard A1 - Groen, Harry J M A1 - Weersma, Rinse K A1 - van den Berg, Leonard H A1 - Wijmenga, Cisca A1 - Ophoff, Roel A A1 - Navis, Gerjan A1 - Rudan, Igor A1 - Snieder, Harold A1 - Wilson, James F A1 - Pramstaller, Peter P A1 - Siscovick, David S A1 - Wang, Thomas J A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Felix, Stephan B A1 - Fishman, Glenn I A1 - Jamshidi, Yalda A1 - Stricker, Bruno H Ch A1 - Samani, Nilesh J A1 - Kääb, Stefan A1 - Arking, Dan E KW - Animals KW - Animals, Newborn KW - Chromosomes, Human KW - Computational Biology KW - Electrocardiography KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Mice KW - Mice, Transgenic KW - Models, Animal KW - Myocytes, Cardiac KW - NAV1.8 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Sodium Channels AB -

The 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.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21076409?dopt=Abstract ER - TY - JOUR T1 - Common variants in KCNN3 are associated with lone atrial fibrillation. JF - Nat Genet Y1 - 2010 A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Glazer, Nicole L A1 - Pfeufer, Arne A1 - Alonso, Alvaro A1 - Chung, Mina K A1 - Sinner, Moritz F A1 - de Bakker, Paul I W A1 - Mueller, Martina A1 - Lubitz, Steven A A1 - Fox, Ervin A1 - Darbar, Dawood A1 - Smith, Nicholas L A1 - Smith, Jonathan D A1 - Schnabel, Renate B A1 - Soliman, Elsayed Z A1 - Rice, Kenneth M A1 - Van Wagoner, David R A1 - Beckmann, Britt-M A1 - van Noord, Charlotte A1 - Wang, Ke A1 - Ehret, Georg B A1 - Rotter, Jerome I A1 - Hazen, Stanley L A1 - Steinbeck, Gerhard A1 - Smith, Albert V A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Makino, Seiko A1 - Nelis, Mari A1 - Milan, David J A1 - Perz, Siegfried A1 - Esko, Tõnu A1 - Köttgen, Anna A1 - Moebus, Susanne A1 - Newton-Cheh, Christopher A1 - Li, Man A1 - Möhlenkamp, Stefan A1 - Wang, Thomas J A1 - Kao, W H Linda A1 - Vasan, Ramachandran S A1 - Nöthen, Markus M A1 - MacRae, Calum A A1 - Stricker, Bruno H Ch A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Boerwinkle, Eric A1 - Metspalu, Andres A1 - Topol, Eric J A1 - Chakravarti, Aravinda A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Witteman, Jacqueline C M A1 - Barnard, John A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Heckbert, Susan R A1 - Kääb, Stefan KW - Adolescent KW - Adult KW - Aged KW - Atrial Fibrillation KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Humans KW - Introns KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Small-Conductance Calcium-Activated Potassium Channels KW - Young Adult AB -

Atrial 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.

VL - 42 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract ER - TY - JOUR T1 - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. JF - Hum Mol Genet Y1 - 2010 A1 - O'Seaghdha, Conall M A1 - Yang, Qiong A1 - Glazer, Nicole L A1 - Leak, Tennille S A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Kao, W H Linda A1 - Lohman, Kurt A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Chen, Yii-Der Ida A1 - Brown, Edward M A1 - Siscovick, David S A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Coresh, Josef A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Liu, Yong Mei A1 - Kestenbaum, Bryan R A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Calcium KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing AB -

Serum 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.

VL - 19 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20705733?dopt=Abstract ER - TY - JOUR T1 - C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. JF - Lancet Y1 - 2010 A1 - Kaptoge, Stephen A1 - Di Angelantonio, Emanuele A1 - Lowe, Gordon A1 - Pepys, Mark B A1 - Thompson, Simon G A1 - Collins, Rory A1 - Danesh, John KW - Alcohol Drinking KW - Biomarkers KW - Blood Pressure KW - Body Mass Index KW - C-Reactive Protein KW - Cholesterol KW - Coronary Disease KW - Databases, Factual KW - Diabetes Mellitus KW - Female KW - Fibrinogen KW - Humans KW - Interleukin-6 KW - Leukocyte Count KW - Lung Diseases KW - Male KW - Middle Aged KW - Motor Activity KW - Neoplasms KW - Regression Analysis KW - Risk Assessment KW - Risk Factors KW - Serum Albumin KW - Sex Factors KW - Smoking KW - Stroke KW - Triglycerides AB -

BACKGROUND: 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.

VL - 375 IS - 9709 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031199?dopt=Abstract ER - TY - JOUR T1 - CRP gene variation and risk of community-acquired pneumonia. JF - Respirology Y1 - 2010 A1 - Mukamal, Kenneth J A1 - Pai, Jennifer K A1 - O'Meara, Ellen S A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Newman, Anne B A1 - Yende, Sachin A1 - Curhan, Gary C A1 - Siscovick, David S A1 - Rimm, Eric B KW - African Americans KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - C-Reactive Protein KW - Cohort Studies KW - Community-Acquired Infections KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Pneumonia KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Smoking AB -

BACKGROUND 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.

VL - 15 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19947988?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and sudden cardiac death risk in the elderly. JF - Circ Cardiovasc Qual Outcomes Y1 - 2010 A1 - Deo, Rajat A1 - Sotoodehnia, Nona A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Chonchol, Michel A1 - Kestenbaum, Bryan A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Age Factors KW - Aged KW - Biomarkers KW - Chi-Square Distribution KW - Creatinine KW - Cystatin C KW - Death, Sudden, Cardiac KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Incidence KW - Kidney Diseases KW - Longitudinal Studies KW - Male KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States KW - Up-Regulation AB -

BACKGROUND: 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.

VL - 3 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20233980?dopt=Abstract ER - TY - JOUR T1 - Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. JF - Lancet Y1 - 2010 A1 - Sarwar, N A1 - Gao, P A1 - Seshasai, S R Kondapally A1 - Gobin, R A1 - Kaptoge, S A1 - Di Angelantonio, E A1 - Ingelsson, E A1 - Lawlor, D A A1 - Selvin, E A1 - Stampfer, M A1 - Stehouwer, C D A A1 - Lewington, S A1 - Pennells, L A1 - Thompson, A A1 - Sattar, N A1 - White, I R A1 - Ray, K K A1 - Danesh, J KW - Adult KW - Aged KW - Blood Glucose KW - Coronary Disease KW - Diabetes Complications KW - Diabetes Mellitus KW - Fasting KW - Female KW - Humans KW - Male KW - Middle Aged KW - Risk Factors KW - Stroke AB -

BACKGROUND: 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.

VL - 375 IS - 9733 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20609967?dopt=Abstract ER - TY - JOUR T1 - European ancestry as a risk factor for atrial fibrillation in African Americans. JF - Circulation Y1 - 2010 A1 - Marcus, Gregory M A1 - Alonso, Alvaro A1 - Peralta, Carmen A A1 - Lettre, Guillaume A1 - Vittinghoff, Eric A1 - Lubitz, Steven A A1 - Fox, Ervin R A1 - Levitzky, Yamini S A1 - Mehra, Reena A1 - Kerr, Kathleen F A1 - Deo, Rajat A1 - Sotoodehnia, Nona A1 - Akylbekova, Meggie A1 - Ellinor, Patrick T A1 - Paltoo, Dina N A1 - Soliman, Elsayed Z A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Atrial Fibrillation KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: 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.

VL - 122 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21098467?dopt=Abstract ER - TY - JOUR T1 - Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. JF - PLoS Genet Y1 - 2010 A1 - Ikram, M Kamran A1 - Sim, Xueling A1 - Xueling, Sim A1 - Jensen, Richard A A1 - Cotch, Mary Frances A1 - Hewitt, Alex W A1 - Ikram, M Arfan A1 - Wang, Jie Jin A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Breteler, Monique M B A1 - Cheung, Ning A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - van Duijn, Cornelia M A1 - Kao, Linda A1 - Cheng, Ching-Yu A1 - Smith, Albert Vernon A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Jonasson, Fridbert A1 - Eiriksdottir, Gudny A1 - Aspelund, Thor A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Li, Xiaohui A1 - Iyengar, Sudha K A1 - Xi, Quansheng A1 - Sivakumaran, Theru A A1 - Mackey, David A A1 - Macgregor, Stuart A1 - Martin, Nicholas G A1 - Young, Terri L A1 - Bis, Josh C A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Hammond, Christopher J A1 - Andrew, Toby A1 - Fahy, Samantha A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Islam, F M Amirul A1 - Rotter, Jerome I A1 - McAuley, Annie K A1 - Boerwinkle, Eric A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Vingerling, Johannes R A1 - Wong, Tien Y KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Child KW - Child, Preschool KW - Chromosomes, Human, Pair 12 KW - Chromosomes, Human, Pair 19 KW - Chromosomes, Human, Pair 5 KW - Chromosomes, Human, Pair 6 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Microcirculation KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Retinal Vessels KW - Young Adult AB -

There 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.

VL - 6 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract ER - TY - JOUR T1 - Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. JF - Hum Mol Genet Y1 - 2010 A1 - McGovern, Dermot P B A1 - Jones, Michelle R A1 - Taylor, Kent D A1 - Marciante, Kristin A1 - Yan, Xiaofei A1 - Dubinsky, Marla A1 - Ippoliti, Andy A1 - Vasiliauskas, Eric A1 - Berel, Dror A1 - Derkowski, Carrie A1 - Dutridge, Deb A1 - Fleshner, Phil A1 - Shih, David Q A1 - Melmed, Gil A1 - Mengesha, Emebet A1 - King, Lily A1 - Pressman, Sheila A1 - Haritunians, Talin A1 - Guo, Xiuqing A1 - Targan, Stephan R A1 - Rotter, Jerome I KW - Adolescent KW - Adult KW - Aged KW - Child KW - Child, Preschool KW - Cohort Studies KW - Crohn Disease KW - Female KW - Fucosyltransferases KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Genetic 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.

VL - 19 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20570966?dopt=Abstract ER - TY - JOUR T1 - Genetic ancestry in lung-function predictions. JF - N Engl J Med Y1 - 2010 A1 - Kumar, Rajesh A1 - Seibold, Max A A1 - Aldrich, Melinda C A1 - Williams, L Keoki A1 - Reiner, Alex P A1 - Colangelo, Laura A1 - Galanter, Joshua A1 - Gignoux, Christopher A1 - Hu, Donglei A1 - Sen, Saunak A1 - Choudhry, Shweta A1 - Peterson, Edward L A1 - Rodriguez-Santana, Jose A1 - Rodriguez-Cintron, William A1 - Nalls, Michael A A1 - Leak, Tennille S A1 - O'Meara, Ellen A1 - Meibohm, Bernd A1 - Kritchevsky, Stephen B A1 - Li, Rongling A1 - Harris, Tamara B A1 - Nickerson, Deborah A A1 - Fornage, Myriam A1 - Enright, Paul A1 - Ziv, Elad A1 - Smith, Lewis J A1 - Liu, Kiang A1 - Burchard, Esteban González KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Female KW - Forced Expiratory Volume KW - Genetic Markers KW - Genotype KW - Humans KW - Linear Models KW - Male KW - Middle Aged KW - Oligonucleotide Array Sequence Analysis KW - Reference Values KW - Respiratory Function Tests KW - Vital Capacity KW - Young Adult AB -

BACKGROUND: 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.)

VL - 363 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20647190?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of medically refractory ulcerative colitis. JF - Inflamm Bowel Dis Y1 - 2010 A1 - Haritunians, Talin A1 - Taylor, Kent D A1 - Targan, Stephan R A1 - Dubinsky, Marla A1 - Ippoliti, Andrew A1 - Kwon, Soonil A1 - Guo, Xiuqing A1 - Melmed, Gil Y A1 - Berel, Dror A1 - Mengesha, Emebet A1 - Psaty, Bruce M A1 - Glazer, Nicole L A1 - Vasiliauskas, Eric A A1 - Rotter, Jerome I A1 - Fleshner, Phillip R A1 - McGovern, Dermot P B KW - Acute Disease KW - Adolescent KW - Adult KW - Cohort Studies KW - Colectomy KW - Colitis, Ulcerative KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Major Histocompatibility Complex KW - Male KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Severity of Illness Index KW - Tumor Necrosis Factor Ligand Superfamily Member 15 KW - Young Adult AB -

BACKGROUND: 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.

VL - 16 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20848476?dopt=Abstract ER - TY - JOUR T1 - Genome-wide analysis of genetic loci associated with Alzheimer disease. JF - JAMA Y1 - 2010 A1 - Seshadri, Sudha A1 - Fitzpatrick, Annette L A1 - Ikram, M Arfan A1 - DeStefano, Anita L A1 - Gudnason, Vilmundur A1 - Boada, Merce A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Carassquillo, Minerva M A1 - Lambert, Jean Charles A1 - Harold, Denise A1 - Schrijvers, Elisabeth M C A1 - Ramirez-Lorca, Reposo A1 - Debette, Stephanie A1 - Longstreth, W T A1 - Janssens, A Cecile J W A1 - Pankratz, V Shane A1 - Dartigues, Jean François A1 - Hollingworth, Paul A1 - Aspelund, Thor A1 - Hernandez, Isabel A1 - Beiser, Alexa A1 - Kuller, Lewis H A1 - Koudstaal, Peter J A1 - Dickson, Dennis W A1 - Tzourio, Christophe A1 - Abraham, Richard A1 - Antunez, Carmen A1 - Du, Yangchun A1 - Rotter, Jerome I A1 - Aulchenko, Yurii S A1 - Harris, Tamara B A1 - Petersen, Ronald C A1 - Berr, Claudine A1 - Owen, Michael J A1 - Lopez-Arrieta, Jesus A1 - Varadarajan, Badri N A1 - Becker, James T A1 - Rivadeneira, Fernando A1 - Nalls, Michael A A1 - Graff-Radford, Neill R A1 - Campion, Dominique A1 - Auerbach, Sanford A1 - Rice, Kenneth A1 - Hofman, Albert A1 - Jonsson, Palmi V A1 - Schmidt, Helena A1 - Lathrop, Mark A1 - Mosley, Thomas H A1 - Au, Rhoda A1 - Psaty, Bruce M A1 - Uitterlinden, André G A1 - Farrer, Lindsay A A1 - Lumley, Thomas A1 - Ruiz, Agustin A1 - Williams, Julie A1 - Amouyel, Philippe A1 - Younkin, Steve G A1 - Wolf, Philip A A1 - Launer, Lenore J A1 - Lopez, Oscar L A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B KW - Age of Onset KW - Aged KW - Alzheimer Disease KW - Case-Control Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

CONTEXT: 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.

VL - 303 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies multiple loci related to resting heart rate. JF - Hum Mol Genet Y1 - 2010 A1 - Eijgelsheim, Mark A1 - Newton-Cheh, Christopher A1 - Sotoodehnia, Nona A1 - de Bakker, Paul I W A1 - Müller, Martina A1 - Morrison, Alanna C A1 - Smith, Albert V A1 - Isaacs, Aaron A1 - Sanna, Serena A1 - Dörr, Marcus A1 - Navarro, Pau A1 - Fuchsberger, Christian A1 - Nolte, Ilja M A1 - de Geus, Eco J C A1 - Estrada, Karol A1 - Hwang, Shih-Jen A1 - Bis, Joshua C A1 - Rückert, Ina-Maria A1 - Alonso, Alvaro A1 - Launer, Lenore J A1 - Hottenga, Jouke Jan A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Rice, Kenneth M A1 - Perz, Siegfried A1 - Arking, Dan E A1 - Spector, Tim D A1 - Kors, Jan A A1 - Aulchenko, Yurii S A1 - Tarasov, Kirill V A1 - Homuth, Georg A1 - Wild, Sarah H A1 - Marroni, Fabio A1 - Gieger, Christian A1 - Licht, Carmilla M A1 - Prineas, Ronald J A1 - Hofman, Albert A1 - Rotter, Jerome I A1 - Hicks, Andrew A A1 - Ernst, Florian A1 - Najjar, Samer S A1 - Wright, Alan F A1 - Peters, Annette A1 - Fox, Ervin R A1 - Oostra, Ben A A1 - Kroemer, Heyo K A1 - Couper, David A1 - Völzke, Henry A1 - Campbell, Harry A1 - Meitinger, Thomas A1 - Uda, Manuela A1 - Witteman, Jacqueline C M A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Harris, Tamara B A1 - Kääb, Stefan A1 - Siscovick, David S A1 - Jamshidi, Yalda A1 - Uitterlinden, André G A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Wilson, James F A1 - Penninx, Brenda W A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Lakatta, Edward G A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Pfeufer, Arne A1 - Heckbert, Susan R A1 - Stricker, Bruno H Ch A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Base Pairing KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Heart Rate KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Rest AB -

Higher 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.

VL - 19 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20639392?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association identifies multiple ulcerative colitis susceptibility loci. JF - Nat Genet Y1 - 2010 A1 - McGovern, Dermot P B A1 - Gardet, Agnès A1 - Törkvist, Leif A1 - Goyette, Philippe A1 - Essers, Jonah A1 - Taylor, Kent D A1 - Neale, Benjamin M A1 - Ong, Rick T H A1 - Lagacé, Caroline A1 - Li, Chun A1 - Green, Todd A1 - Stevens, Christine R A1 - Beauchamp, Claudine A1 - Fleshner, Phillip R A1 - Carlson, Marie A1 - D'Amato, Mauro A1 - Halfvarson, Jonas A1 - Hibberd, Martin L A1 - Lördal, Mikael A1 - Padyukov, Leonid A1 - Andriulli, Angelo A1 - Colombo, Elisabetta A1 - Latiano, Anna A1 - Palmieri, Orazio A1 - Bernard, Edmond-Jean A1 - Deslandres, Colette A1 - Hommes, Daan W A1 - de Jong, Dirk J A1 - Stokkers, Pieter C A1 - Weersma, Rinse K A1 - Sharma, Yashoda A1 - Silverberg, Mark S A1 - Cho, Judy H A1 - Wu, Jing A1 - Roeder, Kathryn A1 - Brant, Steven R A1 - Schumm, L Phillip A1 - Duerr, Richard H A1 - Dubinsky, Marla C A1 - Glazer, Nicole L A1 - Haritunians, Talin A1 - Ippoliti, Andy A1 - Melmed, Gil Y A1 - Siscovick, David S A1 - Vasiliauskas, Eric A A1 - Targan, Stephan R A1 - Annese, Vito A1 - Wijmenga, Cisca A1 - Pettersson, Sven A1 - Rotter, Jerome I A1 - Xavier, Ramnik J A1 - Daly, Mark J A1 - Rioux, John D A1 - Seielstad, Mark KW - Colitis, Ulcerative KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Membrane Proteins KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Receptors, IgG AB -

Ulcerative 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.

VL - 42 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20228799?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. JF - Proc Natl Acad Sci U S A Y1 - 2010 A1 - Levy, Daniel A1 - Neuhausen, Susan L A1 - Hunt, Steven C A1 - Kimura, Masayuki A1 - Hwang, Shih-Jen A1 - Chen, Wei A1 - Bis, Joshua C A1 - Fitzpatrick, Annette L A1 - Smith, Erin A1 - Johnson, Andrew D A1 - Gardner, Jeffrey P A1 - Srinivasan, Sathanur R A1 - Schork, Nicholas A1 - Rotter, Jerome I A1 - Herbig, Utz A1 - Psaty, Bruce M A1 - Sastrasinh, Malinee A1 - Murray, Sarah S A1 - Vasan, Ramachandran S A1 - Province, Michael A A1 - Glazer, Nicole L A1 - Lu, Xiaobin A1 - Cao, Xiaojian A1 - Kronmal, Richard A1 - Mangino, Massimo A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Berenson, Gerald S A1 - Aviv, Abraham KW - Cohort Studies KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocytes KW - Polymorphism, Single Nucleotide KW - Receptors, CXCR4 KW - Telomere KW - Telomere-Binding Proteins AB -

Telomeres 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.

VL - 107 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20421499?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. JF - Stroke Y1 - 2010 A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Sigurdsson, Sigurdur A1 - Heiss, Gerardo A1 - Struchalin, Maksim A1 - Smith, Albert V A1 - van der Lugt, Aad A1 - DeCarli, Charles A1 - Lumley, Thomas A1 - Knopman, David S A1 - Enzinger, Christian A1 - Eiriksdottir, Gudny A1 - Koudstaal, Peter J A1 - DeStefano, Anita L A1 - Psaty, Bruce M A1 - Dufouil, Carole A1 - Catellier, Diane J A1 - Fazekas, Franz A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Beiser, Alexa A1 - Rotter, Jerome I A1 - Tzourio, Christophe A1 - Shibata, Dean K A1 - Tscherner, Maria A1 - Harris, Tamara B A1 - Rivadeneira, Fernando A1 - Atwood, Larry D A1 - Rice, Kenneth A1 - Gottesman, Rebecca F A1 - van Buchem, Mark A A1 - Uitterlinden, André G A1 - Kelly-Hayes, Margaret A1 - Cushman, Mary A1 - Zhu, Yicheng A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Romero, Jose R A1 - Lopez, Oscar A1 - van Duijn, Cornelia M A1 - Au, Rhoda A1 - Heckbert, Susan R A1 - Wolf, Philip A A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Breteler, Monique M B A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Longstreth, W T KW - African Americans KW - Aged KW - Brain KW - Brain Infarction KW - Cohort Studies KW - DNA Mutational Analysis KW - Female KW - Gene Frequency KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genetic Testing KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND 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.

VL - 41 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20044523?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. JF - PLoS Genet Y1 - 2010 A1 - Meyer, Tamra E A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Glazer, Nicole L A1 - Smith, Albert V A1 - van Rooij, Frank J A A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Felix, Janine F A1 - Leak, Tennille S A1 - Harris, Tamara B A1 - Yang, Qiong A1 - Dehghan, Abbas A1 - Aspelund, Thor A1 - Katz, Ronit A1 - Homuth, Georg A1 - Kocher, Thomas A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Gieger, Christian A1 - Prucha, Hanna A1 - Pfeufer, Arne A1 - Meitinger, Thomas A1 - Coresh, Josef A1 - Hofman, Albert A1 - Sarnak, Mark J A1 - Chen, Yii-Der Ida A1 - Uitterlinden, André G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Magnesium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Potassium KW - Sodium AB -

Magnesium, 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.

VL - 6 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. JF - PLoS One Y1 - 2010 A1 - Arking, Dan E A1 - Reinier, Kyndaron A1 - Post, Wendy A1 - Jui, Jonathan A1 - Hilton, Gina A1 - O'Connor, Ashley A1 - Prineas, Ronald J A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Rea, Thomas A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Gregory L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Chakravarti, Aravinda A1 - Chugh, Sumeet S KW - Aged KW - Alleles KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Ethnic Groups KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glypicans KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Oligonucleotide Array Sequence Analysis KW - Oregon KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 5 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20360844?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of PR interval. JF - Nat Genet Y1 - 2010 A1 - Pfeufer, Arne A1 - van Noord, Charlotte A1 - Marciante, Kristin D A1 - Arking, Dan E A1 - Larson, Martin G A1 - Smith, Albert Vernon A1 - Tarasov, Kirill V A1 - Müller, Martina A1 - Sotoodehnia, Nona A1 - Sinner, Moritz F A1 - Verwoert, Germaine C A1 - Li, Man A1 - Kao, W H Linda A1 - Köttgen, Anna A1 - Coresh, Josef A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Kors, Jan A A1 - Stricker, Bruno H C A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Beckmann, Britt M A1 - Sauter, Wiebke A1 - Gieger, Christian A1 - Lubitz, Steven A A1 - Newton-Cheh, Christopher A1 - Wang, Thomas J A1 - Magnani, Jared W A1 - Schnabel, Renate B A1 - Chung, Mina K A1 - Barnard, John A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Vasan, Ramachandran S A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Najjar, Samer S A1 - Lakatta, Edward A1 - Schlessinger, David A1 - Uda, Manuela A1 - Abecasis, Goncalo R A1 - Müller-Myhsok, Bertram A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Chakravarti, Aravinda A1 - Soliman, Elsayed Z A1 - Lunetta, Kathryn L A1 - Perz, Siegfried A1 - Wichmann, H-Erich A1 - Meitinger, Thomas A1 - Levy, Daniel A1 - Gudnason, Vilmundur A1 - Ellinor, Patrick T A1 - Sanna, Serena A1 - Kääb, Stefan A1 - Witteman, Jacqueline C M A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - Aged KW - Atrial Fibrillation KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - Meta-Analysis as Topic AB -

The 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.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. JF - Nat Genet Y1 - 2010 A1 - Franke, Andre A1 - McGovern, Dermot P B A1 - Barrett, Jeffrey C A1 - Wang, Kai A1 - Radford-Smith, Graham L A1 - Ahmad, Tariq A1 - Lees, Charlie W A1 - Balschun, Tobias A1 - Lee, James A1 - Roberts, Rebecca A1 - Anderson, Carl A A1 - Bis, Joshua C A1 - Bumpstead, Suzanne A1 - Ellinghaus, David A1 - Festen, Eleonora M A1 - Georges, Michel A1 - Green, Todd A1 - Haritunians, Talin A1 - Jostins, Luke A1 - Latiano, Anna A1 - Mathew, Christopher G A1 - Montgomery, Grant W A1 - Prescott, Natalie J A1 - Raychaudhuri, Soumya A1 - Rotter, Jerome I A1 - Schumm, Philip A1 - Sharma, Yashoda A1 - Simms, Lisa A A1 - Taylor, Kent D A1 - Whiteman, David A1 - Wijmenga, Cisca A1 - Baldassano, Robert N A1 - Barclay, Murray A1 - Bayless, Theodore M A1 - Brand, Stephan A1 - Büning, Carsten A1 - Cohen, Albert A1 - Colombel, Jean-Frederick A1 - Cottone, Mario A1 - Stronati, Laura A1 - Denson, Ted A1 - De Vos, Martine A1 - D'Inca, Renata A1 - Dubinsky, Marla A1 - Edwards, Cathryn A1 - Florin, Tim A1 - Franchimont, Denis A1 - Gearry, Richard A1 - Glas, Jürgen A1 - Van Gossum, Andre A1 - Guthery, Stephen L A1 - Halfvarson, Jonas A1 - Verspaget, Hein W A1 - Hugot, Jean-Pierre A1 - Karban, Amir A1 - Laukens, Debby A1 - Lawrance, Ian A1 - Lemann, Marc A1 - Levine, Arie A1 - Libioulle, Cecile A1 - Louis, Edouard A1 - Mowat, Craig A1 - Newman, William A1 - Panés, Julián A1 - Phillips, Anne A1 - Proctor, Deborah D A1 - Regueiro, Miguel A1 - Russell, Richard A1 - Rutgeerts, Paul A1 - Sanderson, Jeremy A1 - Sans, Miquel A1 - Seibold, Frank A1 - Steinhart, A Hillary A1 - Stokkers, Pieter C F A1 - Törkvist, Leif A1 - Kullak-Ublick, Gerd A1 - Wilson, David A1 - Walters, Thomas A1 - Targan, Stephan R A1 - Brant, Steven R A1 - Rioux, John D A1 - D'Amato, Mauro A1 - Weersma, Rinse K A1 - Kugathasan, Subra A1 - Griffiths, Anne M A1 - Mansfield, John C A1 - Vermeire, Severine A1 - Duerr, Richard H A1 - Silverberg, Mark S A1 - Satsangi, Jack A1 - Schreiber, Stefan A1 - Cho, Judy H A1 - Annese, Vito A1 - Hakonarson, Hakon A1 - Daly, Mark J A1 - Parkes, Miles KW - Computational Biology KW - Crohn Disease KW - Genetic Linkage KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Reproducibility of Results AB -

We 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.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21102463?dopt=Abstract ER - TY - JOUR T1 - Genomic 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. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Morrison, Alanna C A1 - Felix, Janine F A1 - Cupples, L Adrienne A1 - Glazer, Nicole L A1 - Loehr, Laura R A1 - Dehghan, Abbas A1 - Demissie, Serkalem A1 - Bis, Joshua C A1 - Rosamond, Wayne D A1 - Aulchenko, Yurii S A1 - Wang, Ying A A1 - Haritunians, Talin A1 - Folsom, Aaron R A1 - Rivadeneira, Fernando A1 - Benjamin, Emelia J A1 - Lumley, Thomas A1 - Couper, David A1 - Stricker, Bruno H A1 - O'Donnell, Christopher J A1 - Rice, Kenneth M A1 - Chang, Patricia P A1 - Hofman, Albert A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Fox, Ervin R A1 - Uitterlinden, André G A1 - Wang, Thomas J A1 - Psaty, Bruce M A1 - Willerson, James T A1 - van Duijn, Cornelia M A1 - Boerwinkle, Eric A1 - Witteman, Jacqueline C M A1 - Vasan, Ramachandran S A1 - Smith, Nicholas L KW - African Americans KW - Aged KW - Aged, 80 and over KW - Chemokines KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart Failure KW - Humans KW - Introns KW - Male KW - MARVEL Domain-Containing Proteins KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: 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.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract ER - TY - JOUR T1 - Hip fractures and heart failure: findings from the Cardiovascular Health Study. JF - Eur Heart J Y1 - 2010 A1 - Carbone, Laura A1 - Bůzková, Petra A1 - Fink, Howard A A1 - Lee, Jennifer S A1 - Chen, Zhao A1 - Ahmed, Ali A1 - Parashar, Susmita A1 - Robbins, John R KW - Aged KW - Female KW - Heart Failure KW - Hip Fractures KW - Humans KW - Incidence KW - Male KW - Risk Factors KW - United States AB -

AIMS: 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.

VL - 31 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19892715?dopt=Abstract ER - TY - JOUR T1 - Hundreds of variants clustered in genomic loci and biological pathways affect human height. JF - Nature Y1 - 2010 A1 - Lango Allen, Hana A1 - Estrada, Karol A1 - Lettre, Guillaume A1 - Berndt, Sonja I A1 - Weedon, Michael N A1 - Rivadeneira, Fernando A1 - Willer, Cristen J A1 - Jackson, Anne U A1 - Vedantam, Sailaja A1 - Raychaudhuri, Soumya A1 - Ferreira, Teresa A1 - Wood, Andrew R A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Speliotes, Elizabeth K A1 - Wheeler, Eleanor A1 - Soranzo, Nicole A1 - Park, Ju-Hyun A1 - Yang, Jian A1 - Gudbjartsson, Daniel A1 - Heard-Costa, Nancy L A1 - Randall, Joshua C A1 - Qi, Lu A1 - Vernon Smith, Albert A1 - Mägi, Reedik A1 - Pastinen, Tomi A1 - Liang, Liming A1 - Heid, Iris M A1 - Luan, Jian'an A1 - Thorleifsson, Gudmar A1 - Winkler, Thomas W A1 - Goddard, Michael E A1 - Sin Lo, Ken A1 - Palmer, Cameron A1 - Workalemahu, Tsegaselassie A1 - Aulchenko, Yurii S A1 - Johansson, Asa A1 - Zillikens, M Carola A1 - Feitosa, Mary F A1 - Esko, Tõnu A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Kraft, Peter A1 - Mangino, Massimo A1 - Prokopenko, Inga A1 - Absher, Devin A1 - Albrecht, Eva A1 - Ernst, Florian A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Knowles, Joshua W A1 - Kutalik, Zoltán A1 - Monda, Keri L A1 - Polasek, Ozren A1 - Preuss, Michael A1 - Rayner, Nigel W A1 - Robertson, Neil R A1 - Steinthorsdottir, Valgerdur A1 - Tyrer, Jonathan P A1 - Voight, Benjamin F A1 - Wiklund, Fredrik A1 - Xu, Jianfeng A1 - Zhao, Jing Hua A1 - Nyholt, Dale R A1 - Pellikka, Niina A1 - Perola, Markus A1 - Perry, John R B A1 - Surakka, Ida A1 - Tammesoo, Mari-Liis A1 - Altmaier, Elizabeth L A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Bhangale, Tushar A1 - Boucher, Gabrielle A1 - Chasman, Daniel I A1 - Chen, Constance A1 - Coin, Lachlan A1 - Cooper, Matthew N A1 - Dixon, Anna L A1 - Gibson, Quince A1 - Grundberg, Elin A1 - Hao, Ke A1 - Juhani Junttila, M A1 - Kaplan, Lee M A1 - Kettunen, Johannes A1 - König, Inke R A1 - Kwan, Tony A1 - Lawrence, Robert W A1 - Levinson, Douglas F A1 - Lorentzon, Mattias A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Müller, Martina A1 - Suh Ngwa, Julius A1 - Purcell, Shaun A1 - Rafelt, Suzanne A1 - Salem, Rany M A1 - Salvi, Erika A1 - Sanna, Serena A1 - Shi, Jianxin A1 - Sovio, Ulla A1 - Thompson, John R A1 - Turchin, Michael C A1 - Vandenput, Liesbeth A1 - Verlaan, Dominique J A1 - Vitart, Veronique A1 - White, Charles C A1 - Ziegler, Andreas A1 - Almgren, Peter A1 - Balmforth, Anthony J A1 - Campbell, Harry A1 - Citterio, Lorena A1 - De Grandi, Alessandro A1 - Dominiczak, Anna A1 - Duan, Jubao A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Geus, Eco J C A1 - Glorioso, Nicola A1 - Haiqing, Shen A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Illig, Thomas A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kilpeläinen, Tuomas O A1 - Koiranen, Markku A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Laitinen, Jaana A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Marusic, Ana A1 - Maschio, Andrea A1 - Meitinger, Thomas A1 - Mulas, Antonella A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Petersmann, Astrid A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Rotter, Jerome I A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Schmidt, Carsten Oliver A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Stringham, Heather M A1 - Bragi Walters, G A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Zagato, Laura A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Alavere, Helene A1 - Farrall, Martin A1 - McArdle, Wendy L A1 - Nelis, Mari A1 - Peters, Marjolein J A1 - Ripatti, Samuli A1 - van Meurs, Joyce B J A1 - Aben, Katja K A1 - Ardlie, Kristin G A1 - Beckmann, Jacques S A1 - Beilby, John P A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Collins, Francis S A1 - Cusi, Daniele A1 - den Heijer, Martin A1 - Eiriksdottir, Gudny A1 - Gejman, Pablo V A1 - Hall, Alistair S A1 - Hamsten, Anders A1 - Huikuri, Heikki V A1 - Iribarren, Carlos A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kathiresan, Sekar A1 - Kiemeney, Lambertus A1 - Kocher, Thomas A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Melander, Olle A1 - Mosley, Tom H A1 - Musk, Arthur W A1 - Nieminen, Markku S A1 - O'Donnell, Christopher J A1 - Ohlsson, Claes A1 - Oostra, Ben A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Rioux, John D A1 - Rissanen, Aila A1 - Rivolta, Carlo A1 - Schunkert, Heribert A1 - Shuldiner, Alan R A1 - Siscovick, David S A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - van Ommen, Gert-Jan A1 - Viikari, Jorma A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Province, Michael A A1 - Kayser, Manfred A1 - Arnold, Alice M A1 - Atwood, Larry D A1 - Boerwinkle, Eric A1 - Chanock, Stephen J A1 - Deloukas, Panos A1 - Gieger, Christian A1 - Grönberg, Henrik A1 - Hall, Per A1 - Hattersley, Andrew T A1 - Hengstenberg, Christian A1 - Hoffman, Wolfgang A1 - Lathrop, G Mark A1 - Salomaa, Veikko A1 - Schreiber, Stefan A1 - Uda, Manuela A1 - Waterworth, Dawn A1 - Wright, Alan F A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Hofman, Albert A1 - Mohlke, Karen L A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Cupples, L Adrienne A1 - Erdmann, Jeanette A1 - Fox, Caroline S A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hayes, Richard B A1 - Jarvelin, Marjo-Riitta A1 - Mooser, Vincent A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Wilson, James F A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hu, Frank B A1 - Kaplan, Robert C A1 - Metspalu, Andres A1 - North, Kari E A1 - Schlessinger, David A1 - Wareham, Nicholas J A1 - Hunter, David J A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Wichmann, H-Erich A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Schadt, Eric E A1 - Thorsteinsdottir, Unnur A1 - Peltonen, Leena A1 - Uitterlinden, André G A1 - Visscher, Peter M A1 - Chatterjee, Nilanjan A1 - Loos, Ruth J F A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Lindgren, Cecilia M A1 - Abecasis, Goncalo R A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N KW - Body Height KW - Chromosomes, Human, Pair 3 KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Metabolic Networks and Pathways KW - Multifactorial Inheritance KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Most 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.

VL - 467 IS - 7317 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract ER - TY - JOUR T1 - Impaired kidney function and atrial fibrillation in elderly subjects. JF - J Card Fail Y1 - 2010 A1 - Deo, Rajat A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda A1 - Sarnak, Mark J A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Kidney Function Tests KW - Male AB -

BACKGROUND: 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.

VL - 16 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20123319?dopt=Abstract ER - TY - JOUR T1 - Independent susceptibility markers for atrial fibrillation on chromosome 4q25. JF - Circulation Y1 - 2010 A1 - Lubitz, Steven A A1 - Sinner, Moritz F A1 - Lunetta, Kathryn L A1 - Makino, Seiko A1 - Pfeufer, Arne A1 - Rahman, Rosanna A1 - Veltman, Caroline E A1 - Barnard, John A1 - Bis, Joshua C A1 - Danik, Stephan P A1 - Sonni, Akshata A1 - Shea, Marisa A A1 - Del Monte, Federica A1 - Perz, Siegfried A1 - Müller, Martina A1 - Peters, Annette A1 - Greenberg, Steven M A1 - Furie, Karen L A1 - van Noord, Charlotte A1 - Boerwinkle, Eric A1 - Stricker, Bruno H C A1 - Witteman, Jacqueline A1 - Smith, Jonathan D A1 - Chung, Mina K A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Rosand, Jonathan A1 - Arking, Dan E A1 - Alonso, Alvaro A1 - Kääb, Stefan A1 - Ellinor, Patrick T KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Chromosome Mapping KW - Chromosomes, Human, Pair 4 KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: 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.

VL - 122 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20733104?dopt=Abstract ER - TY - JOUR T1 - Interactions 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. JF - Diabetes Care Y1 - 2010 A1 - Nettleton, Jennifer A A1 - McKeown, Nicola M A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Hivert, Marie-France A1 - Ngwa, Julius A1 - van Rooij, Frank J A A1 - Sonestedt, Emily A1 - Wojczynski, Mary K A1 - Ye, Zheng A1 - Tanaka, Tosh A1 - Garcia, Melissa A1 - Anderson, Jennifer S A1 - Follis, Jack L A1 - Djoussé, Luc A1 - Mukamal, Kenneth A1 - Papoutsakis, Constantina A1 - Mozaffarian, Dariush A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Bennett, Amanda J A1 - Borecki, Ingrid B A1 - Feitosa, Mary F A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Harris, Tamara A1 - Hofman, Albert A1 - Houston, Denise K A1 - Hu, Frank B A1 - Johansson, Ingegerd A1 - Kritchevsky, Stephen B A1 - Langenberg, Claudia A1 - Launer, Lenore A1 - Liu, Yongmei A1 - Loos, Ruth J A1 - Nalls, Michael A1 - Orho-Melander, Marju A1 - Renstrom, Frida A1 - Rice, Kenneth A1 - Riserus, Ulf A1 - Rolandsson, Olov A1 - Rotter, Jerome I A1 - Saylor, Georgia A1 - Sijbrands, Eric J G A1 - Sjogren, Per A1 - Smith, Albert A1 - Steingrímsdóttir, Laufey A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Prokopenko, Inga A1 - Pankow, James S A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Witteman, Jacqueline C M A1 - Dupuis, Josée A1 - Dedoussis, George V A1 - Ordovas, Jose M A1 - Ingelsson, Erik A1 - Cupples, L Adrienne A1 - Siscovick, David S A1 - Franks, Paul W A1 - Meigs, James B KW - Adult KW - Aged KW - Blood Glucose KW - Edible Grain KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE: 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.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20693352?dopt=Abstract ER - TY - JOUR T1 - Intravenous tissue plasminogen activator and stroke in the elderly. JF - Am J Emerg Med Y1 - 2010 A1 - Longstreth, W T A1 - Katz, Ronit A1 - Tirschwell, David L A1 - Cushman, Mary A1 - Psaty, Bruce M KW - Aged, 80 and over KW - Female KW - Fibrinolytic Agents KW - Humans KW - Longitudinal Studies KW - Male KW - Placebos KW - Randomized Controlled Trials as Topic KW - Stroke KW - Tissue Plasminogen Activator KW - Treatment Outcome KW - United States AB -

OBJECTIVE: 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.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20223397?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. JF - Hum Mol Genet Y1 - 2010 A1 - Barbalic, Maja A1 - Dupuis, Josée A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - Hoogeveen, Ron C A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Bretler, Monique A1 - Smith, Nicholas L A1 - Peters, Annette A1 - Lu, Chen A1 - Tracy, Russell P A1 - Aleksic, Nena A1 - Heeriga, Jan A1 - Keaney, John F A1 - Rice, Kenneth A1 - Lip, Gregory Y H A1 - Vasan, Ramachandran S A1 - Glazer, Nicole L A1 - Larson, Martin G A1 - Uitterlinden, André G A1 - Yamamoto, Jennifer A1 - Durda, Peter A1 - Haritunians, Talin A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Hofman, Albert A1 - Koenig, Wolfgang A1 - Jenny, Nancy S A1 - Witteman, Jacqueline C A1 - Ballantyne, Christie A1 - Benjamin, Emelia J KW - ABO Blood-Group System KW - Blood Platelets KW - Enzyme-Linked Immunosorbent Assay KW - European Continental Ancestry Group KW - Fluorescence KW - Genome-Wide Association Study KW - Humans KW - Intercellular Adhesion Molecule-1 KW - P-Selectin AB -

P-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.

VL - 19 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. JF - Lancet Y1 - 2010 A1 - Thompson, Alexander A1 - Gao, Pei A1 - Orfei, Lia A1 - Watson, Sarah A1 - Di Angelantonio, Emanuele A1 - Kaptoge, Stephen A1 - Ballantyne, Christie A1 - Cannon, Christopher P A1 - Criqui, Michael A1 - Cushman, Mary A1 - Hofman, Albert A1 - Packard, Chris A1 - Thompson, Simon G A1 - Collins, Rory A1 - Danesh, John KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Blood Pressure KW - Coronary Disease KW - Female KW - Humans KW - Linear Models KW - Lipids KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Stroke KW - Systole AB -

BACKGROUND: 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.

VL - 375 IS - 9725 U1 - https://www.ncbi.nlm.nih.gov/pubmed/20435228?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and risk of cardiovascular disease in older adults: results from the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2010 A1 - Jenny, Nancy Swords A1 - Solomon, Cam A1 - Cushman, Mary A1 - Tracy, Russell P A1 - Nelson, Jeanenne J A1 - Psaty, Bruce M A1 - Furberg, Curt D KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Female KW - Humans KW - Myocardial Infarction KW - Population Surveillance KW - Prospective Studies KW - Risk KW - Stroke AB -

OBJECTIVE: 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.

VL - 209 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19804884?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. JF - Nat Genet Y1 - 2010 A1 - Hancock, Dana B A1 - Eijgelsheim, Mark A1 - Wilk, Jemma B A1 - Gharib, Sina A A1 - Loehr, Laura R A1 - Marciante, Kristin D A1 - Franceschini, Nora A1 - van Durme, Yannick M T A A1 - Chen, Ting-Hsu A1 - Barr, R Graham A1 - Schabath, Matthew B A1 - Couper, David J A1 - Brusselle, Guy G A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Punjabi, Naresh M A1 - Rivadeneira, Fernando A1 - Morrison, Alanna C A1 - Enright, Paul L A1 - North, Kari E A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Stricker, Bruno H C A1 - O'Connor, George T A1 - London, Stephanie J KW - Databases, Genetic KW - Female KW - Forced Expiratory Volume KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung KW - Lung Diseases KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Spirometry KW - Vital Capacity AB -

Spirometric 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.

VL - 42 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20010835?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. JF - Nat Genet Y1 - 2010 A1 - Heid, Iris M A1 - Jackson, Anne U A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Zillikens, M Carola A1 - Speliotes, Elizabeth K A1 - Mägi, Reedik A1 - Workalemahu, Tsegaselassie A1 - White, Charles C A1 - Bouatia-Naji, Nabila A1 - Harris, Tamara B A1 - Berndt, Sonja I A1 - Ingelsson, Erik A1 - Willer, Cristen J A1 - Weedon, Michael N A1 - Luan, Jian'an A1 - Vedantam, Sailaja A1 - Esko, Tõnu A1 - Kilpeläinen, Tuomas O A1 - Kutalik, Zoltán A1 - Li, Shengxu A1 - Monda, Keri L A1 - Dixon, Anna L A1 - Holmes, Christopher C A1 - Kaplan, Lee M A1 - Liang, Liming A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Molony, Cliona A1 - Nicholson, George A1 - Schadt, Eric E A1 - Zondervan, Krina T A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Lango Allen, Hana A1 - Weyant, Robert J A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Estrada, Karol A1 - Goddard, Michael E A1 - Lettre, Guillaume A1 - Mangino, Massimo A1 - Nyholt, Dale R A1 - Purcell, Shaun A1 - Smith, Albert Vernon A1 - Visscher, Peter M A1 - Yang, Jian A1 - McCarroll, Steven A A1 - Nemesh, James A1 - Voight, Benjamin F A1 - Absher, Devin A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Coin, Lachlan A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kapur, Karen A1 - Ketkar, Shamika A1 - Knowles, Joshua W A1 - Kraft, Peter A1 - Kraja, Aldi T A1 - Lamina, Claudia A1 - Leitzmann, Michael F A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Ong, Ken K A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Rayner, Nigel W A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robertson, Neil R A1 - Sanna, Serena A1 - Sovio, Ulla A1 - Surakka, Ida A1 - Teumer, Alexander A1 - van Wingerden, Sophie A1 - Vitart, Veronique A1 - Zhao, Jing Hua A1 - Cavalcanti-Proença, Christine A1 - Chines, Peter S A1 - Fisher, Eva A1 - Kulzer, Jennifer R A1 - Lecoeur, Cécile A1 - Narisu, Narisu A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Silander, Kaisa A1 - Stark, Klaus A1 - Tammesoo, Mari-Liis A1 - Teslovich, Tanya M A1 - Timpson, Nicholas John A1 - Watanabe, Richard M A1 - Welch, Ryan A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Kettunen, Johannes A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Perola, Markus A1 - Vandenput, Liesbeth A1 - Alavere, Helene A1 - Almgren, Peter A1 - Atwood, Larry D A1 - Bennett, Amanda J A1 - Biffar, Reiner A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Buchanan, Thomas A A1 - Campbell, Harry A1 - Day, Ian N M A1 - Dei, Mariano A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Geus, Eco J C A1 - Gjesing, Anette P A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Havulinna, Aki S A1 - Herzig, Karl-Heinz A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kinnunen, Leena A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kroemer, Heyo K A1 - Krzelj, Vjekoslav A1 - Kuusisto, Johanna A1 - Kvaloy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lathrop, G Mark A1 - Lokki, Marja-Liisa A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - Morken, Mario A A1 - Nelis, Mari A1 - Neville, Matt J A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Strawbridge, Rona J A1 - Stringham, Heather M A1 - Swift, Amy J A1 - Teder-Laving, Maris A1 - Thomson, Brian A1 - Usala, Gianluca A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Volpato, Claudia B A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Beilby, John P A1 - James, Alan L A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Viikari, Jorma A1 - Balkau, Beverley A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Boeing, Heiner A1 - Smith, George Davey A1 - Ebrahim, Shah A1 - Froguel, Philippe A1 - Hansen, Torben A1 - Hengstenberg, Christian A1 - Hveem, Kristian A1 - Isomaa, Bo A1 - Jørgensen, Torben A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Midthjell, Kristian A1 - Pedersen, Oluf A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Wareham, Nicholas J A1 - Arnold, Alice M A1 - Beckmann, Jacques S A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Collins, Francis S A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Hattersley, Andrew T A1 - Hofman, Albert A1 - Hu, Frank B A1 - Illig, Thomas A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Kao, W H Linda A1 - Kaprio, Jaakko A1 - Launer, Lenore J A1 - Munroe, Patricia B A1 - Oostra, Ben A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Syvänen, Ann-Christine A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Völzke, Henry A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Wright, Alan F A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Frayling, Timothy M A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - Hirschhorn, Joel N A1 - Assimes, Themistocles L A1 - Wichmann, H-Erich A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Cupples, L Adrienne A1 - Loos, Ruth J F A1 - Barroso, Inês A1 - McCarthy, Mark I A1 - Fox, Caroline S A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M KW - Adipose Tissue KW - Age Factors KW - Chromosome Mapping KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist-Hip Ratio AB -

Waist-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.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract ER - TY - JOUR T1 - A 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. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Newman, Anne B A1 - Walter, Stefan A1 - Lunetta, Kathryn L A1 - Garcia, Melissa E A1 - Slagboom, P Eline A1 - Christensen, Kaare A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Benjamin, Emelia J A1 - Christiansen, Lene A1 - D'Agostino, Ralph B A1 - Fitzpatrick, Annette L A1 - Franceschini, Nora A1 - Glazer, Nicole L A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Kaplan, Robert A1 - Karasik, David A1 - Kelly-Hayes, Margaret A1 - Kiel, Douglas P A1 - Launer, Lenore J A1 - Marciante, Kristin D A1 - Massaro, Joseph M A1 - Miljkovic, Iva A1 - Nalls, Michael A A1 - Hernandez, Dena A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome A1 - Seshadri, Sudha A1 - Smith, Albert V A1 - Taylor, Kent D A1 - Tiemeier, Henning A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vaupel, James W A1 - Walston, Jeremy A1 - Westendorp, Rudi G J A1 - Harris, Tamara B A1 - Lumley, Thomas A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 65 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract ER - TY - JOUR T1 - Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Yang, Qiong A1 - Köttgen, Anna A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Glazer, Nicole L A1 - Chen, Ming-Huei A1 - Chasman, Daniel I A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore A1 - Nalls, Michael A1 - Hernandez, Dena A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Li, Man A1 - Linda Kao, W H A1 - Chonchol, Michel A1 - Haritunians, Talin A1 - Li, Guo A1 - Lumley, Thomas A1 - Psaty, Bruce M A1 - Shlipak, Michael A1 - Hwang, Shih-Jen A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Upadhyay, Ashish A1 - van Duijn, Cornelia M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Stricker, Bruno A1 - Uitterlinden, André G A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Ridker, Paul M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Fox, Caroline S A1 - Coresh, Josef KW - Cardiovascular Diseases KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Gout KW - Humans KW - Male KW - Risk Factors KW - Uric Acid AB -

BACKGROUND: 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.

VL - 3 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract ER - TY - JOUR T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. JF - Nat Genet Y1 - 2010 A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Prokopenko, Inga A1 - Saxena, Richa A1 - Soranzo, Nicole A1 - Jackson, Anne U A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Gloyn, Anna L A1 - Lindgren, Cecilia M A1 - Mägi, Reedik A1 - Morris, Andrew P A1 - Randall, Joshua A1 - Johnson, Toby A1 - Elliott, Paul A1 - Rybin, Denis A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Henneman, Peter A1 - Grallert, Harald A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Franklin, Christopher S A1 - Navarro, Pau A1 - Song, Kijoung A1 - Goel, Anuj A1 - Perry, John R B A1 - Egan, Josephine M A1 - Lajunen, Taina A1 - Grarup, Niels A1 - Sparsø, Thomas A1 - Doney, Alex A1 - Voight, Benjamin F A1 - Stringham, Heather M A1 - Li, Man A1 - Kanoni, Stavroula A1 - Shrader, Peter A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Qi, Lu A1 - Timpson, Nicholas J A1 - Gieger, Christian A1 - Zabena, Carina A1 - Rocheleau, Ghislain A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Payne, Felicity A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ardlie, Kristin A1 - Ariyurek, Yavuz A1 - Balkau, Beverley A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bonnefond, Amélie A1 - Bonnycastle, Lori L A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Charpentier, Guillaume A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Dina, Christian A1 - Erdos, Michael R A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Fox, Caroline S A1 - Frants, Rune A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Groves, Christopher J A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Gyllensten, Ulf A1 - Hadjadj, Samy A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Herder, Christian A1 - Hicks, Andrew A A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Hui, Jennie A1 - Hung, Joe A1 - Isomaa, Bo A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Lyssenko, Valeriya A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Manning, Alisa K A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McCulloch, Laura J A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Morken, Mario A A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Narisu, Narisu A1 - Neville, Matthew J A1 - Oostra, Ben A A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Palmer, Colin N A A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Rathmann, Wolfgang A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Roden, Michael A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Scott, Laura J A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurethsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tanaka, Toshiko A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - van Hoek, Mandy A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Walters, G Bragi A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Weedon, Michael N A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zeggini, Eleftheria A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Loos, Ruth J F A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Hattersley, Andrew T A1 - Silander, Kaisa A1 - Salomaa, Veikko A1 - Smith, George Davey A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Serrano-Ríos, Manuel A1 - Morris, Andrew D A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pankow, James S A1 - Sampson, Michael J A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Pramstaller, Peter Paul A1 - Wichmann, H Erich A1 - Illig, Thomas A1 - Rudan, Igor A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Campbell, Harry A1 - Wilson, James F A1 - Bergman, Richard N A1 - Buchanan, Thomas A A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Altshuler, David A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Deloukas, Panos A1 - Spector, Timothy D A1 - Frayling, Timothy M A1 - Ferrucci, Luigi A1 - Kong, Augustine A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Aulchenko, Yurii S A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Waterworth, Dawn M A1 - Vollenweider, Peter A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Abecasis, Goncalo R A1 - Wareham, Nicholas J A1 - Sladek, Robert A1 - Froguel, Philippe A1 - Watanabe, Richard M A1 - Meigs, James B A1 - Groop, Leif A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Florez, Jose C A1 - Barroso, Inês KW - Adolescent KW - Adult KW - Alleles KW - Blood Glucose KW - Child KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - DNA Copy Number Variations KW - Fasting KW - Gene Expression Regulation KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

Levels 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.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic 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.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - A novel approach to prediction of mild obstructive sleep disordered breathing in a population-based sample: the Sleep Heart Health Study. JF - Sleep Y1 - 2010 A1 - Caffo, Brian A1 - Diener-West, Marie A1 - Punjabi, Naresh M A1 - Samet, Jonathan KW - Age Factors KW - Aged KW - Algorithms KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Risk Factors KW - ROC Curve KW - Sleep Apnea Syndromes KW - Snoring KW - Waist Circumference AB -

This 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.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21120126?dopt=Abstract ER - TY - JOUR T1 - Novel 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. JF - Circulation Y1 - 2010 A1 - Smith, Nicholas L A1 - Chen, Ming-Huei A1 - Dehghan, Abbas A1 - Strachan, David P A1 - Basu, Saonli A1 - Soranzo, Nicole A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Sabater-Lleal, Maria A1 - Bis, Joshua C A1 - de Maat, Moniek P M A1 - Rumley, Ann A1 - Kong, Xiaoxiao A1 - Yang, Qiong A1 - Williams, Frances M K A1 - Vitart, Veronique A1 - Campbell, Harry A1 - Mälarstig, Anders A1 - Wiggins, Kerri L A1 - van Duijn, Cornelia M A1 - McArdle, Wendy L A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Silveira, Angela A1 - McKnight, Barbara A1 - Uitterlinden, André G A1 - Aleksic, Nena A1 - Meigs, James B A1 - Peters, Annette A1 - Koenig, Wolfgang A1 - Cushman, Mary A1 - Kathiresan, Sekar A1 - Rotter, Jerome I A1 - Bovill, Edwin G A1 - Hofman, Albert A1 - Boerwinkle, Eric A1 - Tofler, Geoffrey H A1 - Peden, John F A1 - Psaty, Bruce M A1 - Leebeek, Frank A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Spector, Timothy D A1 - Wright, Alan F A1 - Wilson, James F A1 - Hamsten, Anders A1 - Lumley, Thomas A1 - Witteman, Jacqueline C M A1 - Tang, Weihong A1 - O'Donnell, Christopher J KW - Adult KW - Factor VII KW - Factor VIII KW - Female KW - Genome-Wide Association Study KW - Hemostasis KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Thrombosis KW - von Willebrand Factor AB -

BACKGROUND: 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.

VL - 121 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20231535?dopt=Abstract ER - TY - JOUR T1 - Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. JF - Am J Respir Crit Care Med Y1 - 2010 A1 - Redline, Susan A1 - Yenokyan, Gayane A1 - Gottlieb, Daniel J A1 - Shahar, Eyal A1 - O'Connor, George T A1 - Resnick, Helaine E A1 - Diener-West, Marie A1 - Sanders, Mark H A1 - Wolf, Philip A A1 - Geraghty, Estella M A1 - Ali, Tauqeer A1 - Lebowitz, Michael A1 - Punjabi, Naresh M KW - Aged KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Proportional Hazards Models KW - Prospective Studies KW - Severity of Illness Index KW - Sex Factors KW - Sleep Apnea, Obstructive KW - Stroke AB -

RATIONALE: 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.

VL - 182 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20339144?dopt=Abstract ER - TY - JOUR T1 - Physical activity and years of healthy life in older adults: results from the cardiovascular health study. JF - J Aging Phys Act Y1 - 2010 A1 - Hirsch, Calvin H A1 - Diehr, Paula A1 - Newman, Anne B A1 - Gerrior, Shirley A A1 - Pratt, Charlotte A1 - Lebowitz, Michael D A1 - Jackson, Sharon A KW - Activities of Daily Living KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Exercise KW - Female KW - Health Behavior KW - Health Status KW - Humans KW - Leisure Activities KW - Life Style KW - Male KW - Quality-Adjusted Life Years KW - Sex Factors AB -

Little 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.

VL - 18 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20651417?dopt=Abstract ER - TY - JOUR T1 - Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. JF - Circulation Y1 - 2010 A1 - Gottlieb, Daniel J A1 - Yenokyan, Gayane A1 - Newman, Anne B A1 - O'Connor, George T A1 - Punjabi, Naresh M A1 - Quan, Stuart F A1 - Redline, Susan A1 - Resnick, Helaine E A1 - Tong, Elisa K A1 - Diener-West, Marie A1 - Shahar, Eyal KW - Adult KW - Aged KW - Coronary Disease KW - Female KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Proportional Hazards Models KW - Prospective Studies KW - Sleep Apnea, Obstructive KW - Survival Analysis AB -

BACKGROUND: 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.

VL - 122 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20625114?dopt=Abstract ER - TY - JOUR T1 - Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. JF - Am J Respir Crit Care Med Y1 - 2010 A1 - Chami, Hassan A A1 - Baldwin, Carol M A1 - Silverman, Angela A1 - Zhang, Ying A1 - Rapoport, David A1 - Punjabi, Naresh M A1 - Gottlieb, Daniel J KW - Aged KW - Disorders of Excessive Somnolence KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Quality of Life KW - Sleep KW - Sleep Apnea Syndromes KW - Sleep, REM AB -

RATIONALE: 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.

VL - 181 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20093641?dopt=Abstract ER - TY - JOUR T1 - Study of the relationship between the interleukin-6 gene and obstructive sleep apnea. JF - Clin Transl Sci Y1 - 2010 A1 - Larkin, Emma K A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Tracy, Russell P A1 - Jenny, Nancy S A1 - Reiner, Alex P A1 - Walston, Jeremy A1 - Redline, Susan KW - Adult KW - African Americans KW - Alleles KW - Female KW - Humans KW - Interleukin-6 KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sleep Apnea, Obstructive VL - 3 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21207764?dopt=Abstract ER - TY - JOUR T1 - Utility of sleep stage transitions in assessing sleep continuity. JF - Sleep Y1 - 2010 A1 - Laffan, Alison A1 - Caffo, Brian A1 - Swihart, Bruce J A1 - Punjabi, Naresh M KW - Age Factors KW - Aged KW - Arousal KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Predictive Value of Tests KW - Risk Factors KW - Sex Factors KW - Sleep Stages KW - Sleep Wake Disorders AB -

STUDY 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.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21120130?dopt=Abstract ER - TY - JOUR T1 - Validation of an atrial fibrillation risk algorithm in whites and African Americans. JF - Arch Intern Med Y1 - 2010 A1 - Schnabel, Renate B A1 - Aspelund, Thor A1 - Li, Guo A1 - Sullivan, Lisa M A1 - Suchy-Dicey, Astrid A1 - Harris, Tamara B A1 - Pencina, Michael J A1 - D'Agostino, Ralph B A1 - Levy, Daniel A1 - Kannel, William B A1 - Wang, Thomas J A1 - Kronmal, Richard A A1 - Wolf, Philip A A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Benjamin, Emelia J A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Atrial Fibrillation KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Electrocardiography KW - Europe KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Hypertension KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Risk Factors KW - Sex Factors KW - Systole KW - United States AB -

BACKGROUND: 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.

VL - 170 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21098350?dopt=Abstract ER - TY - JOUR T1 - Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study. JF - Circ Heart Fail Y1 - 2010 A1 - Kalogeropoulos, Andreas A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Georgiopoulou, Vasiliki A1 - Smith, Andrew L A1 - Smith, Nicholas L A1 - Kritchevsky, Stephen B A1 - Wilson, Peter W F A1 - Newman, Anne B A1 - Harris, Tamara B A1 - Butler, Javed KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Cohort Studies KW - Confidence Intervals KW - Disease Progression KW - Echocardiography, Doppler KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Models, Statistical KW - Predictive Value of Tests KW - Prognosis KW - Severity of Illness Index KW - Sex Distribution KW - Survival Analysis KW - United States AB -

BACKGROUND: 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.

VL - 3 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20427700?dopt=Abstract ER - TY - JOUR T1 - Antihypertensive medication use and change in kidney function in elderly adults: a marginal structural model analysis. JF - Int J Biostat Y1 - 2011 A1 - Odden, Michelle C A1 - Tager, Ira B A1 - van der Laan, Mark J A1 - Delaney, Joseph A C A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Psaty, Bruce M A1 - Shlipak, Michael G KW - Aged KW - Antihypertensive Agents KW - Cystatin C KW - Data Interpretation, Statistical KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney KW - Longitudinal Studies KW - Male KW - Models, Statistical AB -

BACKGROUND: 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.

VL - 7 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22049266?dopt=Abstract ER - TY - JOUR T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. JF - PLoS Genet Y1 - 2011 A1 - Böger, Carsten A A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M A1 - Kutalik, Zoltán A1 - Wichmann, H-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Beckmann, Jacques S A1 - Krämer, Bernhard K A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Kao, W H KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Chronic Disease KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Association Studies KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptor, Epidermal Growth Factor KW - Uromodulin AB -

Family 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.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21980298?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Franceschini, Nora A1 - Carty, Cara A1 - Bůzková, Petra A1 - Reiner, Alex P A1 - Garrett, Tiana A1 - Lin, Yi A1 - Vöckler, Jens-S A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Boerwinkle, Eric A1 - Lin, Dan-Yu A1 - Bookman, Ebony A1 - Best, Lyle G A1 - Bella, Jonathan N A1 - Eaton, Charles A1 - Greenland, Philip A1 - Jenny, Nancy A1 - North, Kari E A1 - Taverna, Darin A1 - Young, Alicia M A1 - Deelman, Ewa A1 - Kooperberg, Charles A1 - Psaty, Bruce A1 - Heiss, Gerardo KW - Aged KW - Aged, 80 and over KW - Continental Population Groups KW - Coronary Disease KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: 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.

VL - 4 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22042884?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. JF - Hum Mol Genet Y1 - 2011 A1 - Fox, Ervin R A1 - Young, J Hunter A1 - Li, Yali A1 - Dreisbach, Albert W A1 - Keating, Brendan J A1 - Musani, Solomon K A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Ganesh, Santhi A1 - Kutlar, Abdullah A1 - Ramachandran, Vasan S A1 - Polak, Josef F A1 - Fabsitz, Richard R A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Redline, Susan A1 - Adeyemo, Adebowale A1 - Hirschorn, Joel N A1 - Sun, Yan V A1 - Wyatt, Sharon B A1 - Penman, Alan D A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Townsend, Raymond R A1 - Doumatey, Ayo P A1 - Tayo, Bamidele O A1 - Mosley, Thomas H A1 - Lyon, Helen N A1 - Kang, Sun J A1 - Rotimi, Charles N A1 - Cooper, Richard S A1 - Franceschini, Nora A1 - Curb, J David A1 - Martin, Lisa W A1 - Eaton, Charles B A1 - Kardia, Sharon L R A1 - Taylor, Herman A A1 - Caulfield, Mark J A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Levy, Daniel KW - Adult KW - African Americans KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

The 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.

VL - 20 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract ER - TY - JOUR T1 - Association 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). JF - Blood Y1 - 2011 A1 - Wassel, Christina L A1 - Lange, Leslie A A1 - Keating, Brendan J A1 - Taylor, Kira C A1 - Johnson, Andrew D A1 - Palmer, Cameron A1 - Ho, Lindsey A A1 - Smith, Nicholas L A1 - Lange, Ethan M A1 - Li, Yun A1 - Yang, Qiong A1 - Delaney, Joseph A A1 - Tang, Weihong A1 - Tofler, Geoffrey A1 - Redline, Susan A1 - Taylor, Herman A A1 - Wilson, James G A1 - Tracy, Russell P A1 - Jacobs, David R A1 - Folsom, Aaron R A1 - Green, David A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Several 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.

VL - 117 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20978265?dopt=Abstract ER - TY - JOUR T1 - Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. JF - Hypertension Y1 - 2011 A1 - Johnson, Andrew D A1 - Newton-Cheh, Christopher A1 - Chasman, Daniel I A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Rose, Lynda A1 - Rice, Kenneth A1 - Verwoert, Germaine C A1 - Launer, Lenore J A1 - Gudnason, Vilmundur A1 - Larson, Martin G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - Caulfield, Mark A1 - van Duijn, Cornelia M A1 - Ridker, Paul M A1 - Munroe, Patricia B A1 - Levy, Daniel KW - Alleles KW - Angiotensinogen KW - Antihypertensive Agents KW - Blood Pressure KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide KW - Receptors, Adrenergic, beta-1 AB -

We 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.

VL - 57 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21444836?dopt=Abstract ER - TY - JOUR T1 - Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. JF - Invest Ophthalmol Vis Sci Y1 - 2011 A1 - Burdon, Kathryn P A1 - Macgregor, Stuart A1 - Bykhovskaya, Yelena A1 - Javadiyan, Sharhbanou A1 - Li, Xiaohui A1 - Laurie, Kate J A1 - Muszynska, Dorota A1 - Lindsay, Richard A1 - Lechner, Judith A1 - Haritunians, Talin A1 - Henders, Anjali K A1 - Dash, Durga A1 - Siscovick, David A1 - Anand, Seema A1 - Aldave, Anthony A1 - Coster, Douglas J A1 - Szczotka-Flynn, Loretta A1 - Mills, Richard A A1 - Iyengar, Sudha K A1 - Taylor, Kent D A1 - Phillips, Tony A1 - Montgomery, Grant W A1 - Rotter, Jerome I A1 - Hewitt, Alex W A1 - Sharma, Shiwani A1 - Rabinowitz, Yaron S A1 - Willoughby, Colin A1 - Craig, Jamie E KW - Adult KW - Aged KW - Chromosomes, Human, Pair 7 KW - Corneal Topography KW - Enzyme-Linked Immunosorbent Assay KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Hepatocyte Growth Factor KW - Humans KW - Keratoconus KW - Middle Aged KW - Nucleic Acid Hybridization KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic KW - Sequence Tagged Sites AB -

PURPOSE: 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.

VL - 52 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22003120?dopt=Abstract ER - TY - JOUR T1 - A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. JF - Diabetes Y1 - 2011 A1 - Kraja, Aldi T A1 - Vaidya, Dhananjay A1 - Pankow, James S A1 - Goodarzi, Mark O A1 - Assimes, Themistocles L A1 - Kullo, Iftikhar J A1 - Sovio, Ulla A1 - Mathias, Rasika A A1 - Sun, Yan V A1 - Franceschini, Nora A1 - Absher, Devin A1 - Li, Guo A1 - Zhang, Qunyuan A1 - Feitosa, Mary F A1 - Glazer, Nicole L A1 - Haritunians, Talin A1 - Hartikainen, Anna-Liisa A1 - Knowles, Joshua W A1 - North, Kari E A1 - Iribarren, Carlos A1 - Kral, Brian A1 - Yanek, Lisa A1 - O'Reilly, Paul F A1 - McCarthy, Mark I A1 - Jaquish, Cashell A1 - Couper, David J A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - Becker, Lewis C A1 - Province, Michael A A1 - Boerwinkle, Eric A1 - Quertermous, Thomas A1 - Palotie, Leena A1 - Jarvelin, Marjo-Riitta A1 - Becker, Diane M A1 - Kardia, Sharon L R A1 - Rotter, Jerome I A1 - Chen, Yii-Der Ida A1 - Borecki, Ingrid B KW - Adult KW - Aged KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Metabolic Syndrome KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE 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.

VL - 60 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21386085?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). JF - Invest Ophthalmol Vis Sci Y1 - 2011 A1 - Sobrin, Lucia A1 - Green, Todd A1 - Sim, Xueling A1 - Jensen, Richard A A1 - Tai, E Shyong A1 - Tay, Wan Ting A1 - Wang, Jie Jin A1 - Mitchell, Paul A1 - Sandholm, Niina A1 - Liu, Yiyuan A1 - Hietala, Kustaa A1 - Iyengar, Sudha K A1 - Brooks, Matthew A1 - Buraczynska, Monika A1 - Van Zuydam, Natalie A1 - Smith, Albert V A1 - Gudnason, Vilmundur A1 - Doney, Alex S F A1 - Morris, Andrew D A1 - Leese, Graham P A1 - Palmer, Colin N A A1 - Swaroop, Anand A1 - Taylor, Herman A A1 - Wilson, James G A1 - Penman, Alan A1 - Chen, Ching J A1 - Groop, Per-Henrik A1 - Saw, Seang-Mei A1 - Aung, Tin A1 - Klein, Barbara E A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Cotch, Mary Frances A1 - Klein, Ronald A1 - Daly, Mark J A1 - Wong, Tien Y KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - Diabetic Nephropathies KW - Diabetic Retinopathy KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Iduronidase KW - Odds Ratio KW - P-Selectin KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

PURPOSE: 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.

VL - 52 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21873659?dopt=Abstract ER - TY - JOUR T1 - Carotid intima-media thickness, electrocardiographic left ventricular hypertrophy, and incidence of intracerebral hemorrhage. JF - Stroke Y1 - 2011 A1 - Folsom, Aaron R A1 - Yatsuya, Hiroshi A1 - Psaty, Bruce M A1 - Shahar, Eyal A1 - Longstreth, W T KW - Carotid Intima-Media Thickness KW - Cerebral Hemorrhage KW - Cohort Studies KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertrophy, Left Ventricular KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND 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.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21940954?dopt=Abstract ER - TY - JOUR T1 - Cerivastatin, genetic variants, and the risk of rhabdomyolysis. JF - Pharmacogenet Genomics Y1 - 2011 A1 - Marciante, Kristin D A1 - Durda, Jon P A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rice, Ken A1 - McKnight, Barbara A1 - Totah, Rheem A A1 - Tamraz, Bani A1 - Kroetz, Deanna L A1 - Fukushima, Hisayo A1 - Kaspera, Rüdiger A1 - Bis, Joshua C A1 - Glazer, Nicole L A1 - Li, Guo A1 - Austin, Thomas R A1 - Taylor, Kent D A1 - Rotter, Jerome I A1 - Jaquish, Cashell E A1 - Kwok, Pui-Yan A1 - Tracy, Russell P A1 - Psaty, Bruce M KW - Adult KW - Aged KW - Aged, 80 and over KW - Aryl Hydrocarbon Hydroxylases KW - Case-Control Studies KW - Cytochrome P-450 CYP2C8 KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Glucuronosyltransferase KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Male KW - Middle Aged KW - Organic Anion Transporters KW - Polymorphism, Single Nucleotide KW - Pyridines KW - Rhabdomyolysis KW - Risk KW - Ryanodine Receptor Calcium Release Channel KW - Solute Carrier Organic Anion Transporter Family Member 1b1 AB -

OBJECTIVE: 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.

VL - 21 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21386754?dopt=Abstract ER - TY - JOUR T1 - Comparison of characteristics and outcomes of asymptomatic versus symptomatic left ventricular dysfunction in subjects 65 years old or older (from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2011 A1 - Pandhi, Jay A1 - Gottdiener, John S A1 - Bartz, Traci M A1 - Kop, Willem J A1 - Mehra, Mandeep R KW - Aged KW - Female KW - Heart Failure, Systolic KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - Ultrasonography KW - Ventricular Dysfunction, Left AB -

Although 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.

VL - 107 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21575752?dopt=Abstract ER - TY - JOUR T1 - The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study. JF - BMC Cardiovasc Disord Y1 - 2011 A1 - Shiffman, Dov A1 - O'Meara, Ellen S A1 - Rowland, Charles M A1 - Louie, Judy Z A1 - Cushman, Mary A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Case-Control Studies KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Variation KW - Humans KW - Kinesin KW - Male KW - Myocardial Infarction KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: 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.

VL - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21406102?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification 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.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - Cystatin C identifies chronic kidney disease patients at higher risk for complications. JF - J Am Soc Nephrol Y1 - 2011 A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Ix, Joachim A1 - Fried, Linda F A1 - de Boer, Ian A1 - Palmas, Walter A1 - Siscovick, David A1 - Levey, Andrew S A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Chronic Disease KW - Creatinine KW - Cystatin C KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Retrospective Studies KW - Risk Factors AB -

Although 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.

VL - 22 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21164029?dopt=Abstract ER - TY - JOUR T1 - Depressive symptoms, physical inactivity and risk of cardiovascular mortality in older adults: the Cardiovascular Health Study. JF - Heart Y1 - 2011 A1 - Win, Sithu A1 - Parakh, Kapil A1 - Eze-Nliam, Chete M A1 - Gottdiener, John S A1 - Kop, Willem J A1 - Ziegelstein, Roy C KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Depression KW - Epidemiologic Methods KW - Female KW - Humans KW - Male KW - Motor Activity KW - Psychiatric Status Rating Scales KW - United States AB -

BACKGROUND: 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.

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21339320?dopt=Abstract ER - TY - JOUR T1 - Electrocardiographic and clinical predictors separating atherosclerotic sudden cardiac death from incident coronary heart disease. JF - Heart Y1 - 2011 A1 - Soliman, Elsayed Z A1 - Prineas, Ronald J A1 - Case, L Douglas A1 - Russell, Gregory A1 - Rosamond, Wayne A1 - Rea, Thomas A1 - Sotoodehnia, Nona A1 - Post, Wendy S A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Burke, Gregory L KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Continental Population Groups KW - Coronary Disease KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Ethnic Groups KW - Female KW - Heart Rate KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Risk Adjustment KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: 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.

VL - 97 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21775508?dopt=Abstract ER - TY - JOUR T1 - Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. JF - PLoS Genet Y1 - 2011 A1 - Pasaniuc, Bogdan A1 - Zaitlen, Noah A1 - Lettre, Guillaume A1 - Chen, Gary K A1 - Tandon, Arti A1 - Kao, W H Linda A1 - Ruczinski, Ingo A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Zhu, Xiaofeng A1 - Larkin, Emma A1 - Lange, Leslie A A1 - Cupples, L Adrienne A1 - Yang, Qiong A1 - Akylbekova, Ermeg L A1 - Musani, Solomon K A1 - Divers, Jasmin A1 - Mychaleckyj, Joe A1 - Li, Mingyao A1 - Papanicolaou, George J A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - John, Esther M A1 - Bernstein, Leslie A1 - Zheng, Wei A1 - Hu, Jennifer J A1 - Ziegler, Regina G A1 - Nyante, Sarah J A1 - Bandera, Elisa V A1 - Ingles, Sue A A1 - Press, Michael F A1 - Chanock, Stephen J A1 - Deming, Sandra L A1 - Rodriguez-Gil, Jorge L A1 - Palmer, Cameron D A1 - Buxbaum, Sarah A1 - Ekunwe, Lynette A1 - Hirschhorn, Joel N A1 - Henderson, Brian E A1 - Myers, Simon A1 - Haiman, Christopher A A1 - Reich, David A1 - Patterson, Nick A1 - Wilson, James G A1 - Price, Alkes L KW - African Americans KW - Algorithms KW - Breast Neoplasms KW - Chromosome Mapping KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Male KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Receptor, Fibroblast Growth Factor, Type 2 KW - Software AB -

While 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.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21541012?dopt=Abstract ER - TY - JOUR T1 - Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults. JF - Stroke Y1 - 2011 A1 - Thacker, Evan L A1 - Psaty, Bruce M A1 - McKnight, Barbara A1 - Heckbert, Susan R A1 - Longstreth, W T A1 - Mukamal, Kenneth J A1 - Meigs, James B A1 - de Boer, Ian H A1 - Boyko, Edward J A1 - Carnethon, Mercedes R A1 - Kizer, Jorge R A1 - Tracy, Russell P A1 - Smith, Nicholas L A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Body Mass Index KW - Brain Ischemia KW - Fasting KW - Female KW - Humans KW - Incidence KW - Insulin Resistance KW - Male KW - Risk KW - Stroke AB -

BACKGROUND 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.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21998054?dopt=Abstract ER - TY - JOUR T1 - Gait speed and survival in older adults. JF - JAMA Y1 - 2011 A1 - Studenski, Stephanie A1 - Perera, Subashan A1 - Patel, Kushang A1 - Rosano, Caterina A1 - Faulkner, Kimberly A1 - Inzitari, Marco A1 - Brach, Jennifer A1 - Chandler, Julie A1 - Cawthon, Peggy A1 - Connor, Elizabeth Barrett A1 - Nevitt, Michael A1 - Visser, Marjolein A1 - Kritchevsky, Stephen A1 - Badinelli, Stefania A1 - Harris, Tamara A1 - Newman, Anne B A1 - Cauley, Jane A1 - Ferrucci, Luigi A1 - Guralnik, Jack KW - Aged KW - Cohort Studies KW - Female KW - Gait KW - Geriatric Assessment KW - Humans KW - Life Expectancy KW - Male KW - Survival Analysis KW - United States AB -

CONTEXT: 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.

VL - 305 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21205966?dopt=Abstract ER - TY - JOUR T1 - Gender differences between the Minnesota code and Novacode electrocardiographic prognostication of coronary heart disease in the cardiovascular health study. JF - Am J Cardiol Y1 - 2011 A1 - Zhang, Zhu-Ming A1 - Prineas, Ronald J A1 - Case, Doug A1 - Psaty, Bruce M A1 - Suzuki, Takeki A1 - Burke, Gregory L KW - Aged KW - Coronary Disease KW - Electrocardiography KW - Female KW - Humans KW - Incidence KW - Male KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - United States AB -

The 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.

VL - 107 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21247534?dopt=Abstract ER - TY - JOUR T1 - Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. JF - PLoS Genet Y1 - 2011 A1 - Liu, Ching-Ti A1 - Garnaas, Maija K A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Franceschini, Nora A1 - Peralta, Carmen A A1 - de Boer, Ian H A1 - Lu, Xiaoning A1 - Atkinson, Elizabeth A1 - Ding, Jingzhong A1 - Nalls, Michael A1 - Shriner, Daniel A1 - Coresh, Josef A1 - Kutlar, Abdullah A1 - Bibbins-Domingo, Kirsten A1 - Siscovick, David A1 - Akylbekova, Ermeg A1 - Wyatt, Sharon A1 - Astor, Brad A1 - Mychaleckjy, Josef A1 - Li, Man A1 - Reilly, Muredach P A1 - Townsend, Raymond R A1 - Adeyemo, Adebowale A1 - Zonderman, Alan B A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Mosley, Thomas H A1 - Harris, Tamara B A1 - Rotimi, Charles N A1 - Liu, Yongmei A1 - Kardia, Sharon L R A1 - Evans, Michele K A1 - Shlipak, Michael G A1 - Kramer, Holly A1 - Flessner, Michael F A1 - Dreisbach, Albert W A1 - Goessling, Wolfram A1 - Cupples, L Adrienne A1 - Kao, W Linda A1 - Fox, Caroline S KW - Adaptor Proteins, Vesicular Transport KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Animals KW - Female KW - Gene Knockdown Techniques KW - Genetic Association Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - KCNQ1 Potassium Channel KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Neoplasm Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Zebrafish AB -

Chronic 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.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21931561?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. JF - PLoS Genet Y1 - 2011 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Taylor, Kira A1 - Schumacher, Fredrick R A1 - Hindorff, Lucia A A1 - Ambite, José L A1 - Anderson, Garnet A1 - Best, Lyle G A1 - Brown-Gentry, Kristin A1 - Bůzková, Petra A1 - Carlson, Christopher S A1 - Cochran, Barbara A1 - Cole, Shelley A A1 - Devereux, Richard B A1 - Duggan, Dave A1 - Eaton, Charles B A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Haessler, Jeff A1 - Howard, Barbara V A1 - Johnson, Karen C A1 - Laston, Sandra A1 - Kolonel, Laurence N A1 - Lee, Elisa T A1 - MacCluer, Jean W A1 - Manolio, Teri A A1 - Pendergrass, Sarah A A1 - Quibrera, Miguel A1 - Shohet, Ralph V A1 - Wilkens, Lynne R A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Crawford, Dana C KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Continental Population Groups KW - Female KW - Gene Frequency KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Lipid Metabolism KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Male KW - Middle Aged KW - Molecular Epidemiology KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Triglycerides KW - Young Adult AB -

For 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.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738485?dopt=Abstract ER - TY - JOUR T1 - Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. JF - PLoS Genet Y1 - 2011 A1 - Lemaitre, Rozenn N A1 - Tanaka, Toshiko A1 - Tang, Weihong A1 - Manichaikul, Ani A1 - Foy, Millennia A1 - Kabagambe, Edmond K A1 - Nettleton, Jennifer A A1 - King, Irena B A1 - Weng, Lu-Chen A1 - Bhattacharya, Sayanti A1 - Bandinelli, Stefania A1 - Bis, Joshua C A1 - Rich, Stephen S A1 - Jacobs, David R A1 - Cherubini, Antonio A1 - McKnight, Barbara A1 - Liang, Shuang A1 - Gu, Xiangjun A1 - Rice, Kenneth A1 - Laurie, Cathy C A1 - Lumley, Thomas A1 - Browning, Brian L A1 - Psaty, Bruce M A1 - Chen, Yii-der I A1 - Friedlander, Yechiel A1 - Djoussé, Luc A1 - Wu, Jason H Y A1 - Siscovick, David S A1 - Uitterlinden, André G A1 - Arnett, Donna K A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Tsai, Michael Y A1 - Mozaffarian, Dariush A1 - Steffen, Lyn M KW - Alleles KW - Continental Population Groups KW - Fatty Acids, Omega-3 KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide AB -

Long-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.

VL - 7 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21829377?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of fibrin D-dimer levels in healthy adults. JF - Circulation Y1 - 2011 A1 - Smith, Nicholas L A1 - Huffman, Jennifer E A1 - Strachan, David P A1 - Huang, Jie A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Shin, So-Youn A1 - Baumert, Jens A1 - Vitart, Veronique A1 - Bis, Joshua C A1 - Wild, Sarah H A1 - Rumley, Ann A1 - Yang, Qiong A1 - Uitterlinden, André G A1 - Stott, David J A1 - Davies, Gail A1 - Carter, Angela M A1 - Thorand, Barbara A1 - Polasek, Ozren A1 - McKnight, Barbara A1 - Campbell, Harry A1 - Rudnicka, Alicja R A1 - Chen, Ming-Huei A1 - Buckley, Brendan M A1 - Harris, Sarah E A1 - Peters, Annette A1 - Pulanic, Drazen A1 - Lumley, Thomas A1 - de Craen, Anton J M A1 - Liewald, David C A1 - Gieger, Christian A1 - Campbell, Susan A1 - Ford, Ian A1 - Gow, Alan J A1 - Luciano, Michelle A1 - Porteous, David J A1 - Guo, Xiuqing A1 - Sattar, Naveed A1 - Tenesa, Albert A1 - Cushman, Mary A1 - Slagboom, P Eline A1 - Visscher, Peter M A1 - Spector, Tim D A1 - Illig, Thomas A1 - Rudan, Igor A1 - Bovill, Edwin G A1 - Wright, Alan F A1 - McArdle, Wendy L A1 - Tofler, Geoffrey A1 - Hofman, Albert A1 - Westendorp, Rudi G J A1 - Starr, John M A1 - Grant, Peter J A1 - Karakas, Mahir A1 - Hastie, Nicholas D A1 - Psaty, Bruce M A1 - Wilson, James F A1 - Lowe, Gordon D O A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Jukema, J Wouter A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Koenig, Wolfgang A1 - Hayward, Caroline KW - Adult KW - Aged KW - Blood Coagulation KW - European Continental Ancestry Group KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Testing KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Reference Values KW - Thromboplastin AB -

BACKGROUND: 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.

VL - 123 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract ER - TY - JOUR T1 - Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. JF - Nature Y1 - 2011 A1 - Ehret, Georg B A1 - Munroe, Patricia B A1 - Rice, Kenneth M A1 - Bochud, Murielle A1 - Johnson, Andrew D A1 - Chasman, Daniel I A1 - Smith, Albert V A1 - Tobin, Martin D A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Pihur, Vasyl A1 - Vollenweider, Peter A1 - O'Reilly, Paul F A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Launer, Lenore A1 - Zhao, Jing Hua A1 - Aulchenko, Yurii A1 - Heath, Simon A1 - Sõber, Siim A1 - Parsa, Afshin A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Dehghan, Abbas A1 - Zhang, Feng A1 - Lucas, Gavin A1 - Hicks, Andrew A A1 - Jackson, Anne U A1 - Peden, John F A1 - Tanaka, Toshiko A1 - Wild, Sarah H A1 - Rudan, Igor A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Parker, Alex N A1 - Fava, Cristiano A1 - Chambers, John C A1 - Fox, Ervin R A1 - Kumari, Meena A1 - Go, Min Jin A1 - van der Harst, Pim A1 - Kao, Wen Hong Linda A1 - Sjögren, Marketa A1 - Vinay, D G A1 - Alexander, Myriam A1 - Tabara, Yasuharu A1 - Shaw-Hawkins, Sue A1 - Whincup, Peter H A1 - Liu, Yongmei A1 - Shi, Gang A1 - Kuusisto, Johanna A1 - Tayo, Bamidele A1 - Seielstad, Mark A1 - Sim, Xueling A1 - Nguyen, Khanh-Dung Hoang A1 - Lehtimäki, Terho A1 - Matullo, Giuseppe A1 - Wu, Ying A1 - Gaunt, Tom R A1 - Onland-Moret, N Charlotte A1 - Cooper, Matthew N A1 - Platou, Carl G P A1 - Org, Elin A1 - Hardy, Rebecca A1 - Dahgam, Santosh A1 - Palmen, Jutta A1 - Vitart, Veronique A1 - Braund, Peter S A1 - Kuznetsova, Tatiana A1 - Uiterwaal, Cuno S P M A1 - Adeyemo, Adebowale A1 - Palmas, Walter A1 - Campbell, Harry A1 - Ludwig, Barbara A1 - Tomaszewski, Maciej A1 - Tzoulaki, Ioanna A1 - Palmer, Nicholette D A1 - Aspelund, Thor A1 - Garcia, Melissa A1 - Chang, Yen-Pei C A1 - O'Connell, Jeffrey R A1 - Steinle, Nanette I A1 - Grobbee, Diederick E A1 - Arking, Dan E A1 - Kardia, Sharon L A1 - Morrison, Alanna C A1 - Hernandez, Dena A1 - Najjar, Samer A1 - McArdle, Wendy L A1 - Hadley, David A1 - Brown, Morris J A1 - Connell, John M A1 - Hingorani, Aroon D A1 - Day, Ian N M A1 - Lawlor, Debbie A A1 - Beilby, John P A1 - Lawrence, Robert W A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Dreisbach, Albert W A1 - Li, Yali A1 - Young, J Hunter A1 - Bis, Joshua C A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Adair, Linda S A1 - Lee, Nanette R A1 - Chen, Ming-Huei A1 - Olden, Matthias A1 - Pattaro, Cristian A1 - Bolton, Judith A Hoffman A1 - Köttgen, Anna A1 - Bergmann, Sven A1 - Mooser, Vincent A1 - Chaturvedi, Nish A1 - Frayling, Timothy M A1 - Islam, Muhammad A1 - Jafar, Tazeen H A1 - Erdmann, Jeanette A1 - Kulkarni, Smita R A1 - Bornstein, Stefan R A1 - Grässler, Jürgen A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Kettunen, Johannes A1 - Howard, Philip A1 - Taylor, Andrew A1 - Guarrera, Simonetta A1 - Ricceri, Fulvio A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Weder, Alan B A1 - Hunt, Steven C A1 - Sun, Yan V A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Bonnycastle, Lori L A1 - Scott, Laura J A1 - Stringham, Heather M A1 - Peltonen, Leena A1 - Perola, Markus A1 - Vartiainen, Erkki A1 - Brand, Stefan-Martin A1 - Staessen, Jan A A1 - Wang, Thomas J A1 - Burton, Paul R A1 - Soler Artigas, Maria A1 - Dong, Yanbin A1 - Snieder, Harold A1 - Wang, Xiaoling A1 - Zhu, Haidong A1 - Lohman, Kurt K A1 - Rudock, Megan E A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Doumatey, Ayo A1 - Shriner, Daniel A1 - Veldre, Gudrun A1 - Viigimaa, Margus A1 - Kinra, Sanjay A1 - Prabhakaran, Dorairaj A1 - Tripathy, Vikal A1 - Langefeld, Carl D A1 - Rosengren, Annika A1 - Thelle, Dag S A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - Forrester, Terrence A1 - Hilton, Gina A1 - McKenzie, Colin A A1 - Salako, Tunde A1 - Iwai, Naoharu A1 - Kita, Yoshikuni A1 - Ogihara, Toshio A1 - Ohkubo, Takayoshi A1 - Okamura, Tomonori A1 - Ueshima, Hirotsugu A1 - Umemura, Satoshi A1 - Eyheramendy, Susana A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Cho, Yoon Shin A1 - Kim, Hyung-Lae A1 - Lee, Jong-Young A1 - Scott, James A1 - Sehmi, Joban S A1 - Zhang, Weihua A1 - Hedblad, Bo A1 - Nilsson, Peter A1 - Smith, George Davey A1 - Wong, Andrew A1 - Narisu, Narisu A1 - Stančáková, Alena A1 - Raffel, Leslie J A1 - Yao, Jie A1 - Kathiresan, Sekar A1 - O'Donnell, Christopher J A1 - Schwartz, Stephen M A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Shrine, Nick R G A1 - Wain, Louise V A1 - Morken, Mario A A1 - Swift, Amy J A1 - Laitinen, Jaana A1 - Prokopenko, Inga A1 - Zitting, Paavo A1 - Cooper, Jackie A A1 - Humphries, Steve E A1 - Danesh, John A1 - Rasheed, Asif A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Bakker, Stephan J L A1 - van Gilst, Wiek H A1 - Janipalli, Charles S A1 - Mani, K Radha A1 - Yajnik, Chittaranjan S A1 - Hofman, Albert A1 - Mattace-Raso, Francesco U S A1 - Oostra, Ben A A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Rivadeneira, Fernando A1 - Lakatta, Edward G A1 - Orrù, Marco A1 - Scuteri, Angelo A1 - Ala-Korpela, Mika A1 - Kangas, Antti J A1 - Lyytikäinen, Leo-Pekka A1 - Soininen, Pasi A1 - Tukiainen, Taru A1 - Würtz, Peter A1 - Ong, Rick Twee-Hee A1 - Dörr, Marcus A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Zelenika, Diana A1 - Deloukas, Panos A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Zhai, Guangju A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Terzic, Janos A1 - Kumar, M V Kranthi A1 - Denniff, Matthew A1 - Zukowska-Szczechowska, Ewa A1 - Wagenknecht, Lynne E A1 - Fowkes, F Gerald R A1 - Charchar, Fadi J A1 - Schwarz, Peter E H A1 - Hayward, Caroline A1 - Guo, Xiuqing A1 - Rotimi, Charles A1 - Bots, Michiel L A1 - Brand, Eva A1 - Samani, Nilesh J A1 - Polasek, Ozren A1 - Talmud, Philippa J A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Laan, Maris A1 - Hveem, Kristian A1 - Palmer, Lyle J A1 - van der Schouw, Yvonne T A1 - Casas, Juan P A1 - Mohlke, Karen L A1 - Vineis, Paolo A1 - Raitakari, Olli A1 - Ganesh, Santhi K A1 - Wong, Tien Y A1 - Tai, E Shyong A1 - Cooper, Richard S A1 - Laakso, Markku A1 - Rao, Dabeeru C A1 - Harris, Tamara B A1 - Morris, Richard W A1 - Dominiczak, Anna F A1 - Kivimaki, Mika A1 - Marmot, Michael G A1 - Miki, Tetsuro A1 - Saleheen, Danish A1 - Chandak, Giriraj R A1 - Coresh, Josef A1 - Navis, Gerjan A1 - Salomaa, Veikko A1 - Han, Bok-Ghee A1 - Zhu, Xiaofeng A1 - Kooner, Jaspal S A1 - Melander, Olle A1 - Ridker, Paul M A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wright, Alan F A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Farrall, Martin A1 - Tuomilehto, Jaakko A1 - Pramstaller, Peter P A1 - Elosua, Roberto A1 - Soranzo, Nicole A1 - Sijbrands, Eric J G A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Shuldiner, Alan R A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Rettig, Rainer A1 - Uda, Manuela A1 - Strachan, David P A1 - Witteman, Jacqueline C M A1 - Hartikainen, Anna-Liisa A1 - Beckmann, Jacques S A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Boehnke, Michael A1 - Larson, Martin G A1 - Jarvelin, Marjo-Riitta A1 - Psaty, Bruce M A1 - Abecasis, Goncalo R A1 - Chakravarti, Aravinda A1 - Elliott, Paul A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Caulfield, Mark J A1 - Johnson, Toby KW - Africa KW - Asia KW - Blood Pressure KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - Europe KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Kidney Diseases KW - Polymorphism, Single Nucleotide KW - Stroke AB -

Blood 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.

VL - 478 IS - 7367 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract ER - TY - JOUR T1 - Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. JF - Brain Y1 - 2011 A1 - Schmidt, Helena A1 - Zeginigg, Marion A1 - Wiltgen, Marco A1 - Freudenberger, Paul A1 - Petrovic, Katja A1 - Cavalieri, Margherita A1 - Gider, Pierre A1 - Enzinger, Christian A1 - Fornage, Myriam A1 - Debette, Stephanie A1 - Rotter, Jerome I A1 - Ikram, Mohammad A A1 - Launer, Lenore J A1 - Schmidt, Reinhold KW - Aged KW - Aged, 80 and over KW - Alleles KW - Brain KW - Cerebral Small Vessel Diseases KW - Exons KW - Female KW - Follow-Up Studies KW - Genetic Association Studies KW - Genotype KW - Humans KW - Hypertension KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Phenotype KW - Promoter Regions, Genetic KW - Prospective Studies KW - Receptor, Notch3 KW - Receptors, Notch AB -

Cerebral 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.

VL - 134 IS - Pt 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22006983?dopt=Abstract ER - TY - JOUR T1 - Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. JF - Nat Genet Y1 - 2011 A1 - Kilpeläinen, Tuomas O A1 - Zillikens, M Carola A1 - Stančáková, Alena A1 - Finucane, Francis M A1 - Ried, Janina S A1 - Langenberg, Claudia A1 - Zhang, Weihua A1 - Beckmann, Jacques S A1 - Luan, Jian'an A1 - Vandenput, Liesbeth A1 - Styrkarsdottir, Unnur A1 - Zhou, Yanhua A1 - Smith, Albert Vernon A1 - Zhao, Jing-Hua A1 - Amin, Najaf A1 - Vedantam, Sailaja A1 - Shin, So-Youn A1 - Haritunians, Talin A1 - Fu, Mao A1 - Feitosa, Mary F A1 - Kumari, Meena A1 - Halldorsson, Bjarni V A1 - Tikkanen, Emmi A1 - Mangino, Massimo A1 - Hayward, Caroline A1 - Song, Ci A1 - Arnold, Alice M A1 - Aulchenko, Yurii S A1 - Oostra, Ben A A1 - Campbell, Harry A1 - Cupples, L Adrienne A1 - Davis, Kathryn E A1 - Döring, Angela A1 - Eiriksdottir, Gudny A1 - Estrada, Karol A1 - Fernández-Real, José Manuel A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Glazer, Nicole L A1 - Guiducci, Candace A1 - Hofman, Albert A1 - Humphries, Steve E A1 - Isomaa, Bo A1 - Jacobs, Leonie C A1 - Jula, Antti A1 - Karasik, David A1 - Karlsson, Magnus K A1 - Khaw, Kay-Tee A1 - Kim, Lauren J A1 - Kivimaki, Mika A1 - Klopp, Norman A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Liu, Yongmei A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - McKnight, Barbara A1 - Mellström, Dan A1 - Mitchell, Braxton D A1 - Mooser, Vincent A1 - Moreno, José Maria A1 - Männistö, Satu A1 - O'Connell, Jeffery R A1 - Pascoe, Laura A1 - Peltonen, Leena A1 - Peral, Belén A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Salomaa, Veikko A1 - Savage, David B A1 - Semple, Robert K A1 - Skaric-Juric, Tatjana A1 - Sigurdsson, Gunnar A1 - Song, Kijoung S A1 - Spector, Timothy D A1 - Syvänen, Ann-Christine A1 - Talmud, Philippa J A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Vidal-Puig, Antonio A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Clegg, Deborah J A1 - Schadt, Eric A1 - Wilson, James F A1 - Rudan, Igor A1 - Ripatti, Samuli A1 - Borecki, Ingrid B A1 - Shuldiner, Alan R A1 - Ingelsson, Erik A1 - Jansson, John-Olov A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Groop, Leif A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando A1 - Walker, Mark A1 - Barroso, Inês A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Chambers, John C A1 - Kooner, Jaspal S A1 - Soranzo, Nicole A1 - Hirschhorn, Joel N A1 - Stefansson, Kari A1 - Wichmann, H-Erich A1 - Ohlsson, Claes A1 - O'Rahilly, Stephen A1 - Wareham, Nicholas J A1 - Speliotes, Elizabeth K A1 - Fox, Caroline S A1 - Laakso, Markku A1 - Loos, Ruth J F KW - Adiponectin KW - Adiposity KW - Alleles KW - Body Fat Distribution KW - Body Mass Index KW - Body Weight KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Insulin Receptor Substrate Proteins KW - Intracellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Meta-Analysis as Topic KW - Metabolome KW - Obesity KW - Polymorphism, Single Nucleotide KW - Subcutaneous Fat AB -

Genome-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.

VL - 43 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21706003?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. JF - PLoS Genet Y1 - 2011 A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Rose, Lynda A1 - Barbalic, Maja A1 - Dupuis, Josée A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - Benjamin, Emelia J A1 - Shiffman, Dov A1 - Parker, Alexander N A1 - Chasman, Daniel I KW - ABO Blood-Group System KW - Cohort Studies KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - I-kappa B Kinase KW - Intercellular Adhesion Molecule-1 KW - Lipase KW - Membrane Proteins KW - Models, Genetic KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide KW - Proteins KW - Transcription Factor RelA AB -

Soluble 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.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21533024?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. JF - Nat Genet Y1 - 2011 A1 - Soler Artigas, Maria A1 - Loth, Daan W A1 - Wain, Louise V A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Tang, Wenbo A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Smith, Albert Vernon A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Jackson, Catherine M A1 - Evans, David M A1 - Cadby, Gemma A1 - Fornage, Myriam A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Johnson, Toby A1 - Aldrich, Melinda C A1 - Aspelund, Thor A1 - Barroso, Inês A1 - Campbell, Harry A1 - Cassano, Patricia A A1 - Couper, David J A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Gislason, Gauti Kjartan A1 - Grkovic, Ivica A1 - Hammond, Christopher J A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Ramasamy, Adaikalavan A1 - Heckbert, Susan R A1 - Heliövaara, Markku A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - James, Alan L A1 - Jankovic, Stipan A1 - Joubert, Bonnie R A1 - Karrasch, Stefan A1 - Klopp, Norman A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Launer, Lenore J A1 - Liu, Yongmei A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lumley, Thomas A1 - Al Balushi, Khalid A A1 - Ang, Wei Q A1 - Barr, R Graham A1 - Beilby, John A1 - Blakey, John D A1 - Boban, Mladen A1 - Boraska, Vesna A1 - Brisman, Jonas A1 - Britton, John R A1 - Brusselle, Guy G A1 - Cooper, Cyrus A1 - Curjuric, Ivan A1 - Dahgam, Santosh A1 - Deary, Ian J A1 - Ebrahim, Shah A1 - Eijgelsheim, Mark A1 - Francks, Clyde A1 - Gaysina, Darya A1 - Granell, Raquel A1 - Gu, Xiangjun A1 - Hankinson, John L A1 - Hardy, Rebecca A1 - Harris, Sarah E A1 - Henderson, John A1 - Henry, Amanda A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Holt, Patrick G A1 - Hui, Jennie A1 - Hunter, Michael L A1 - Imboden, Medea A1 - Jameson, Karen A A1 - Kerr, Shona M A1 - Kolcic, Ivana A1 - Kronenberg, Florian A1 - Liu, Jason Z A1 - Marchini, Jonathan A1 - McKeever, Tricia A1 - Morris, Andrew D A1 - Olin, Anna-Carin A1 - Porteous, David J A1 - Postma, Dirkje S A1 - Rich, Stephen S A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Sayer, Avan Aihie A1 - Sayers, Ian A1 - Sly, Peter D A1 - Smith, George Davey A1 - Sood, Akshay A1 - Starr, John M A1 - Uitterlinden, André G A1 - Vonk, Judith M A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Wong, Andrew A1 - Mangino, Massimo A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - North, Kari E A1 - Omenaas, Ernst A1 - Palmer, Lyle J A1 - Pietiläinen, Kirsi H A1 - Pin, Isabelle A1 - Pola Sbreve Ek, Ozren A1 - Pouta, Anneli A1 - Psaty, Bruce M A1 - Hartikainen, Anna-Liisa A1 - Rantanen, Taina A1 - Ripatti, Samuli A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rudnicka, Alicja R A1 - Schulz, Holger A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Warrington, Nicole M A1 - Wichmann, H-Erich A1 - Wild, Sarah H A1 - Wilk, Jemma B A1 - Wjst, Matthias A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Pennell, Craig E A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Holloway, John W A1 - Boezen, H Marike A1 - Lawlor, Debbie A A1 - Morris, Richard W A1 - Probst-Hensch, Nicole A1 - Kaprio, Jaakko A1 - Wilson, James F A1 - Hayward, Caroline A1 - Kähönen, Mika A1 - Heinrich, Joachim A1 - Musk, Arthur W A1 - Jarvis, Deborah L A1 - Gläser, Sven A1 - Jarvelin, Marjo-Riitta A1 - Ch Stricker, Bruno H A1 - Elliott, Paul A1 - O'Connor, George T A1 - Strachan, David P A1 - London, Stephanie J A1 - Hall, Ian P A1 - Gudnason, Vilmundur A1 - Tobin, Martin D KW - Child KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests AB -

Pulmonary 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.

VL - 43 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. JF - Ann Neurol Y1 - 2011 A1 - Fornage, Myriam A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Dufouil, Carole A1 - Sigurdsson, Sigurdur A1 - Lumley, Thomas A1 - DeStefano, Anita L A1 - Fazekas, Franz A1 - Vrooman, Henri A A1 - Shibata, Dean K A1 - Maillard, Pauline A1 - Zijdenbos, Alex A1 - Smith, Albert V A1 - Gudnason, Haukur A1 - de Boer, Renske A1 - Cushman, Mary A1 - Mazoyer, Bernard A1 - Heiss, Gerardo A1 - Vernooij, Meike W A1 - Enzinger, Christian A1 - Glazer, Nicole L A1 - Beiser, Alexa A1 - Knopman, David S A1 - Cavalieri, Margherita A1 - Niessen, Wiro J A1 - Harris, Tamara B A1 - Petrovic, Katja A1 - Lopez, Oscar L A1 - Au, Rhoda A1 - Lambert, Jean-Charles A1 - Hofman, Albert A1 - Gottesman, Rebecca F A1 - Garcia, Melissa A1 - Heckbert, Susan R A1 - Atwood, Larry D A1 - Catellier, Diane J A1 - Uitterlinden, André G A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Aspelund, Thor A1 - Romero, Jose R A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Nalls, Michael A A1 - Rotter, Jerome I A1 - Sharrett, Richey A1 - van Duijn, Cornelia M A1 - Amouyel, Philippe A1 - Wolf, Philip A A1 - Gudnason, Vilmundur A1 - van der Lugt, Aad A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Tzourio, Christophe A1 - Breteler, Monique M B A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Longstreth, W T A1 - DeCarli, Charles A1 - Launer, Lenore J KW - Aged KW - Aged, 80 and over KW - Cerebral Cortex KW - Chromosomes, Human, Pair 17 KW - Cognition Disorders KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukoencephalopathies KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Movement Disorders KW - Nerve Fibers, Myelinated KW - Polymorphism, Single Nucleotide KW - Residence Characteristics KW - RNA, Messenger AB -

OBJECTIVE: 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.

VL - 69 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. JF - Hum Mol Genet Y1 - 2011 A1 - Tin, Adrienne A1 - Woodward, Owen M A1 - Kao, Wen Hong Linda A1 - Liu, Ching-Ti A1 - Lu, Xiaoning A1 - Nalls, Michael A A1 - Shriner, Daniel A1 - Semmo, Mariam A1 - Akylbekova, Ermeg L A1 - Wyatt, Sharon B A1 - Hwang, Shih-Jen A1 - Yang, Qiong A1 - Zonderman, Alan B A1 - Adeyemo, Adebowale A A1 - Palmer, Cameron A1 - Meng, Yan A1 - Reilly, Muredach A1 - Shlipak, Michael G A1 - Siscovick, David A1 - Evans, Michele K A1 - Rotimi, Charles N A1 - Flessner, Michael F A1 - Köttgen, Michael A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - African Americans KW - Aged KW - Animals KW - CHO Cells KW - Cricetinae KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Gout KW - Humans KW - Loss of Heterozygosity KW - Male KW - Middle Aged KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Polymorphism, Single Nucleotide KW - Uric Acid KW - Young Adult AB -

Serum 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.

VL - 20 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. JF - Hum Mol Genet Y1 - 2011 A1 - Kaplan, Robert C A1 - Petersen, Ann-Kristin A1 - Chen, Ming-Huei A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Döring, Angela A1 - Lam, Carolyn S P A1 - Friedrich, Nele A1 - Newman, Anne A1 - Müller, Martina A1 - Yang, Qiong A1 - Homuth, Georg A1 - Cappola, Anne A1 - Klopp, Norman A1 - Smith, Holly A1 - Ernst, Florian A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Sawyer, Douglas B A1 - Biffar, Reiner A1 - Rotter, Jerome I A1 - Gieger, Christian A1 - Sullivan, Lisa S A1 - Völzke, Henry A1 - Rice, Kenneth A1 - Spyroglou, Ariadni A1 - Kroemer, Heyo K A1 - Ida Chen, Y-D A1 - Manolopoulou, Jenny A1 - Nauck, Matthias A1 - Strickler, Howard D A1 - Goodarzi, Mark O A1 - Reincke, Martin A1 - Pollak, Michael N A1 - Bidlingmaier, Martin A1 - Vasan, Ramachandran S A1 - Wallaschofski, Henri KW - Aged KW - Chromosomes, Human, Pair 7 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Polymorphism, Single Nucleotide AB -

Insulin-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.

VL - 20 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. JF - Nat Genet Y1 - 2011 A1 - Wain, Louise V A1 - Verwoert, Germaine C A1 - O'Reilly, Paul F A1 - Shi, Gang A1 - Johnson, Toby A1 - Johnson, Andrew D A1 - Bochud, Murielle A1 - Rice, Kenneth M A1 - Henneman, Peter A1 - Smith, Albert V A1 - Ehret, Georg B A1 - Amin, Najaf A1 - Larson, Martin G A1 - Mooser, Vincent A1 - Hadley, David A1 - Dörr, Marcus A1 - Bis, Joshua C A1 - Aspelund, Thor A1 - Esko, Tõnu A1 - Janssens, A Cecile J W A1 - Zhao, Jing Hua A1 - Heath, Simon A1 - Laan, Maris A1 - Fu, Jingyuan A1 - Pistis, Giorgio A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Lucas, Gavin A1 - Pirastu, Nicola A1 - Pichler, Irene A1 - Jackson, Anne U A1 - Webster, Rebecca J A1 - Zhang, Feng A1 - Peden, John F A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Campbell, Harry A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Hottenga, Jouke-Jan A1 - Vitart, Veronique A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Bragg-Gresham, Jennifer L A1 - Alizadeh, Behrooz Z A1 - Chambers, John C A1 - Guo, Xiuqing A1 - Lehtimäki, Terho A1 - Kuhnel, Brigitte A1 - Lopez, Lorna M A1 - Polasek, Ozren A1 - Boban, Mladen A1 - Nelson, Christopher P A1 - Morrison, Alanna C A1 - Pihur, Vasyl A1 - Ganesh, Santhi K A1 - Hofman, Albert A1 - Kundu, Suman A1 - Mattace-Raso, Francesco U S A1 - Rivadeneira, Fernando A1 - Sijbrands, Eric J G A1 - Uitterlinden, André G A1 - Hwang, Shih-Jen A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Zitting, Paavo A1 - McArdle, Wendy L A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Glazer, Nicole L A1 - Taylor, Kent D A1 - Harris, Tamara B A1 - Alavere, Helene A1 - Haller, Toomas A1 - Keis, Aime A1 - Tammesoo, Mari-Liis A1 - Aulchenko, Yurii A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Eyheramendy, Susana A1 - Org, Elin A1 - Sõber, Siim A1 - Lu, Xiaowen A1 - Nolte, Ilja M A1 - Penninx, Brenda W A1 - Corre, Tanguy A1 - Masciullo, Corrado A1 - Sala, Cinzia A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Melander, Olle A1 - O'Donnell, Christopher J A1 - Salomaa, Veikko A1 - d'Adamo, Adamo Pio A1 - Fabretto, Antonella A1 - Faletra, Flavio A1 - Ulivi, Sheila A1 - Del Greco, Fabiola M A1 - Facheris, Maurizio A1 - Collins, Francis S A1 - Bergman, Richard N A1 - Beilby, John P A1 - Hung, Joseph A1 - Musk, A William A1 - Mangino, Massimo A1 - Shin, So-Youn A1 - Soranzo, Nicole A1 - Watkins, Hugh A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Gider, Pierre A1 - Loitfelder, Marisa A1 - Zeginigg, Marion A1 - Hernandez, Dena A1 - Najjar, Samer S A1 - Navarro, Pau A1 - Wild, Sarah H A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - de Geus, Eco J C A1 - Willemsen, Gonneke A1 - Parker, Alex N A1 - Rose, Lynda M A1 - Buckley, Brendan A1 - Stott, David A1 - Orrù, Marco A1 - Uda, Manuela A1 - van der Klauw, Melanie M A1 - Zhang, Weihua A1 - Li, Xinzhong A1 - Scott, James A1 - Chen, Yii-Der Ida A1 - Burke, Gregory L A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Döring, Angela A1 - Meitinger, Thomas A1 - Davies, Gail A1 - Starr, John M A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Lindeman, Jan H A1 - Hoen, Peter A C 't A1 - König, Inke R A1 - Felix, Janine F A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Breteler, Monique A1 - Debette, Stephanie A1 - DeStefano, Anita L A1 - Fornage, Myriam A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Holm, Hilma A1 - Stefansson, Kari A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Samani, Nilesh J A1 - Preuss, Michael A1 - Rudan, Igor A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Wichmann, H-Erich A1 - Raitakari, Olli T A1 - Palmas, Walter A1 - Kooner, Jaspal S A1 - Stolk, Ronald P A1 - Jukema, J Wouter A1 - Wright, Alan F A1 - Boomsma, Dorret I A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Schmidt, Reinhold A1 - Farrall, Martin A1 - Spector, Tim D A1 - Palmer, Lyle J A1 - Tuomilehto, Jaakko A1 - Pfeufer, Arne A1 - Gasparini, Paolo A1 - Siscovick, David A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Toniolo, Daniela A1 - Snieder, Harold A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Wareham, Nicholas J A1 - Oostra, Ben A A1 - Metspalu, Andres A1 - Launer, Lenore A1 - Rettig, Rainer A1 - Strachan, David P A1 - Beckmann, Jacques S A1 - Witteman, Jacqueline C M A1 - Erdmann, Jeanette A1 - van Dijk, Ko Willems A1 - Boerwinkle, Eric A1 - Boehnke, Michael A1 - Ridker, Paul M A1 - Jarvelin, Marjo-Riitta A1 - Chakravarti, Aravinda A1 - Abecasis, Goncalo R A1 - Gudnason, Vilmundur A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Caulfield, Mark J A1 - Rao, Dabeeru C A1 - Tobin, Martin D A1 - Elliott, Paul A1 - van Duijn, Cornelia M KW - Arteries KW - Blood Pressure KW - Case-Control Studies KW - Follow-Up Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide AB -

Numerous 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.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of aging. JF - Neurobiol Aging Y1 - 2011 A1 - Walter, Stefan A1 - Atzmon, Gil A1 - Demerath, Ellen W A1 - Garcia, Melissa E A1 - Kaplan, Robert C A1 - Kumari, Meena A1 - Lunetta, Kathryn L A1 - Milaneschi, Yuri A1 - Tanaka, Toshiko A1 - Tranah, Gregory J A1 - Völker, Uwe A1 - Yu, Lei A1 - Arnold, Alice A1 - Benjamin, Emelia J A1 - Biffar, Reiner A1 - Buchman, Aron S A1 - Boerwinkle, Eric A1 - Couper, David A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Harris, Tamara B A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Karasik, David A1 - Kiel, Douglas P A1 - Kocher, Thomas A1 - Kuningas, Maris A1 - Launer, Lenore J A1 - Lohman, Kurt K A1 - Lutsey, Pamela L A1 - Mackenbach, Johan A1 - Marciante, Kristin A1 - Psaty, Bruce M A1 - Reiman, Eric M A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Shardell, Michelle D A1 - Smith, Albert V A1 - van Duijn, Cornelia A1 - Walston, Jeremy A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Baumeister, Sebastian E A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Liu, Yongmei A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Franceschini, Nora KW - Aging KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity AB -

Human 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.

VL - 32 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract ER - TY - JOUR T1 - Health and function of participants in the Long Life Family Study: A comparison with other cohorts. JF - Aging (Albany NY) Y1 - 2011 A1 - Newman, Anne B A1 - Glynn, Nancy W A1 - Taylor, Christopher A A1 - Sebastiani, Paola A1 - Perls, Thomas T A1 - Mayeux, Richard A1 - Christensen, Kaare A1 - Zmuda, Joseph M A1 - Barral, Sandra A1 - Lee, Joseph H A1 - Simonsick, Eleanor M A1 - Walston, Jeremy D A1 - Yashin, Anatoli I A1 - Hadley, Evan KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Gait KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Psychomotor Performance KW - Research Design AB -

Individuals 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.

VL - 3 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21258136?dopt=Abstract ER - TY - JOUR T1 - Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. JF - PLoS Genet Y1 - 2011 A1 - Arking, Dan E A1 - Junttila, M Juhani A1 - Goyette, Philippe A1 - Huertas-Vazquez, Adriana A1 - Eijgelsheim, Mark A1 - Blom, Marieke T A1 - Newton-Cheh, Christopher A1 - Reinier, Kyndaron A1 - Teodorescu, Carmen A1 - Uy-Evanado, Audrey A1 - Carter-Monroe, Naima A1 - Kaikkonen, Kari S A1 - Kortelainen, Marja-Leena A1 - Boucher, Gabrielle A1 - Lagacé, Caroline A1 - Moes, Anna A1 - Zhao, XiaoQing A1 - Kolodgie, Frank A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Uitterlinden, André G A1 - Marsman, Roos F A1 - Pazoki, Raha A1 - Bardai, Abdennasser A1 - Koster, Rudolph W A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Bhatnagar, Pallav A1 - Post, Wendy A1 - Hilton, Gina A1 - Prineas, Ronald J A1 - Li, Man A1 - Köttgen, Anna A1 - Ehret, Georg A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Kao, W H Linda A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Greg L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Cupples, L Adrienne A1 - Jui, Jonathan A1 - Gunson, Karen A1 - Kesaniemi, Y Antero A1 - Wilde, Arthur A M A1 - Tardif, Jean-Claude A1 - O'Donnell, Christopher J A1 - Bezzina, Connie R A1 - Virmani, Renu A1 - Stricker, Bruno H C H A1 - Tan, Hanno L A1 - Albert, Christine M A1 - Chakravarti, Aravinda A1 - Rioux, John D A1 - Huikuri, Heikki V A1 - Chugh, Sumeet S KW - Adult KW - Aged KW - Alleles KW - Chromosomes, Human, Pair 2 KW - Death, Sudden, Cardiac KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Contraction KW - Polymorphism, Single Nucleotide AB -

Sudden 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).

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738491?dopt=Abstract ER - TY - JOUR T1 - The Impact of Sleep-Disordered Breathing on Body Mass Index (BMI): The Sleep Heart Health Study (SHHS). JF - Southwest J Pulm Crit Care Y1 - 2011 A1 - Brown, Mark A A1 - Goodwin, James L A1 - Silva, Graciela E A1 - Behari, Ajay A1 - Newman, Anne B A1 - Punjabi, Naresh M A1 - Resnick, Helaine E A1 - Robbins, John A A1 - Quan, Stuart F AB -

INTRODUCTION: 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.

VL - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22288025?dopt=Abstract ER - TY - JOUR T1 - Kidney function decline in the elderly: impact of lipoprotein-associated phospholipase A(2). JF - Am J Nephrol Y1 - 2011 A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Shlipak, Michael A1 - Dubin, Ruth A1 - DeBoer, Ian A1 - Jenny, Nancy A1 - Fitzpatrick, Annette A1 - Koro, Carol A1 - Kestenbaum, Bryan A1 - Ix, Joachim A1 - Sarnak, Mark A1 - Cushman, Mary KW - Aged KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Disease Progression KW - Female KW - Geriatrics KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Middle Aged KW - Phospholipases A2 KW - Risk Factors KW - Treatment Outcome AB -

BACKGROUND: 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.

VL - 34 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22056971?dopt=Abstract ER - TY - JOUR T1 - Leukocyte telomere length and mortality in the Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2011 A1 - Fitzpatrick, Annette L A1 - Kronmal, Richard A A1 - Kimura, Masayuki A1 - Gardner, Jeffrey P A1 - Psaty, Bruce M A1 - Jenny, Nancy S A1 - Tracy, Russell P A1 - Hardikar, Sheetal A1 - Aviv, Abraham KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Mass Index KW - Cardiovascular Diseases KW - Cause of Death KW - Comorbidity KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Humans KW - Hypertension KW - Leukocytes KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Smoking KW - Stroke KW - Telomere AB -

BACKGROUND: 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.

VL - 66 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21289018?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study. JF - Diabetologia Y1 - 2011 A1 - Nelson, T L A1 - Kamineni, A A1 - Psaty, B A1 - Cushman, M A1 - Jenny, N S A1 - Hokanson, J A1 - Furberg, C A1 - Mukamal, K J KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

AIMS/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.

VL - 54 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21103980?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients. JF - Genet Epidemiol Y1 - 2011 A1 - Manning, Alisa K A1 - LaValley, Michael A1 - Liu, Ching-Ti A1 - Rice, Kenneth A1 - An, Ping A1 - Liu, Yongmei A1 - Miljkovic, Iva A1 - Rasmussen-Torvik, Laura A1 - Harris, Tamara B A1 - Province, Michael A A1 - Borecki, Ingrid B A1 - Florez, Jose C A1 - Meigs, James B A1 - Cupples, L Adrienne A1 - Dupuis, Josée KW - Adult KW - Aged KW - Body Mass Index KW - Confidence Intervals KW - Diabetes Mellitus, Type 2 KW - Environment KW - Fasting KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Insulin KW - Least-Squares Analysis KW - Male KW - Mathematical Computing KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - PPAR gamma AB -

INTRODUCTION: 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.

VL - 35 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21181894?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. JF - Nat Genet Y1 - 2011 A1 - Bis, Joshua C A1 - Kavousi, Maryam A1 - Franceschini, Nora A1 - Isaacs, Aaron A1 - Abecasis, Goncalo R A1 - Schminke, Ulf A1 - Post, Wendy S A1 - Smith, Albert V A1 - Cupples, L Adrienne A1 - Markus, Hugh S A1 - Schmidt, Reinhold A1 - Huffman, Jennifer E A1 - Lehtimäki, Terho A1 - Baumert, Jens A1 - Münzel, Thomas A1 - Heckbert, Susan R A1 - Dehghan, Abbas A1 - North, Kari A1 - Oostra, Ben A1 - Bevan, Steve A1 - Stoegerer, Eva-Maria A1 - Hayward, Caroline A1 - Raitakari, Olli A1 - Meisinger, Christa A1 - Schillert, Arne A1 - Sanna, Serena A1 - Völzke, Henry A1 - Cheng, Yu-Ching A1 - Thorsson, Bolli A1 - Fox, Caroline S A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Nambi, Vijay A1 - Halperin, Eran A1 - Petrovic, Katja E A1 - Peltonen, Leena A1 - Wichmann, H Erich A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Parsa, Afshin A1 - Aspelund, Thor A1 - Demissie, Serkalem A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Taylor, Kent A1 - Uitterlinden, Andre A1 - Couper, David J A1 - Sitzer, Matthias A1 - Kähönen, Mika A1 - Illig, Thomas A1 - Wild, Philipp S A1 - Orrù, Marco A1 - Lüdemann, Jan A1 - Shuldiner, Alan R A1 - Eiriksdottir, Gudny A1 - White, Charles C A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Seissler, Jochen A1 - Zeller, Tanja A1 - Usala, Gianluca A1 - Ernst, Florian A1 - Launer, Lenore J A1 - D'Agostino, Ralph B A1 - O'Leary, Daniel H A1 - Ballantyne, Christie A1 - Thiery, Joachim A1 - Ziegler, Andreas A1 - Lakatta, Edward G A1 - Chilukoti, Ravi Kumar A1 - Harris, Tamara B A1 - Wolf, Philip A A1 - Psaty, Bruce M A1 - Polak, Joseph F A1 - Li, Xia A1 - Rathmann, Wolfgang A1 - Uda, Manuela A1 - Boerwinkle, Eric A1 - Klopp, Norman A1 - Schmidt, Helena A1 - Wilson, James F A1 - Viikari, Jorma A1 - Koenig, Wolfgang A1 - Blankenberg, Stefan A1 - Newman, Anne B A1 - Witteman, Jacqueline A1 - Heiss, Gerardo A1 - Duijn, Cornelia van A1 - Scuteri, Angelo A1 - Homuth, Georg A1 - Mitchell, Braxton D A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Aging KW - Atherosclerosis KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Middle Aged KW - Phenotype KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Carotid 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.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. JF - Circulation Y1 - 2011 A1 - Dehghan, Abbas A1 - Dupuis, Josée A1 - Barbalic, Maja A1 - Bis, Joshua C A1 - Eiriksdottir, Gudny A1 - Lu, Chen A1 - Pellikka, Niina A1 - Wallaschofski, Henri A1 - Kettunen, Johannes A1 - Henneman, Peter A1 - Baumert, Jens A1 - Strachan, David P A1 - Fuchsberger, Christian A1 - Vitart, Veronique A1 - Wilson, James F A1 - Paré, Guillaume A1 - Naitza, Silvia A1 - Rudock, Megan E A1 - Surakka, Ida A1 - de Geus, Eco J C A1 - Alizadeh, Behrooz Z A1 - Guralnik, Jack A1 - Shuldiner, Alan A1 - Tanaka, Toshiko A1 - Zee, Robert Y L A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Kavousi, Maryam A1 - Ripatti, Samuli A1 - Nauck, Matthias A1 - Smith, Nicholas L A1 - Smith, Albert V A1 - Sundvall, Jouko A1 - Scheet, Paul A1 - Liu, Yongmei A1 - Ruokonen, Aimo A1 - Rose, Lynda M A1 - Larson, Martin G A1 - Hoogeveen, Ron C A1 - Freimer, Nelson B A1 - Teumer, Alexander A1 - Tracy, Russell P A1 - Launer, Lenore J A1 - Buring, Julie E A1 - Yamamoto, Jennifer F A1 - Folsom, Aaron R A1 - Sijbrands, Eric J G A1 - Pankow, James A1 - Elliott, Paul A1 - Keaney, John F A1 - Sun, Wei A1 - Sarin, Antti-Pekka A1 - Fontes, João D A1 - Badola, Sunita A1 - Astor, Brad C A1 - Hofman, Albert A1 - Pouta, Anneli A1 - Werdan, Karl A1 - Greiser, Karin H A1 - Kuss, Oliver A1 - Meyer zu Schwabedissen, Henriette E A1 - Thiery, Joachim A1 - Jamshidi, Yalda A1 - Nolte, Ilja M A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Parker, Alexander N A1 - Aspelund, Thor A1 - Bates, David A1 - Young, Lauren A1 - Tsui, Kim A1 - Siscovick, David S A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Uda, Manuela A1 - Schlessinger, David A1 - Rudan, Igor A1 - Hicks, Andrew A A1 - Penninx, Brenda W A1 - Thorand, Barbara A1 - Gieger, Christian A1 - Coresh, Joe A1 - Willemsen, Gonneke A1 - Harris, Tamara B A1 - Uitterlinden, André G A1 - Jarvelin, Marjo-Riitta A1 - Rice, Kenneth A1 - Radke, Dörte A1 - Salomaa, Veikko A1 - Willems van Dijk, Ko A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Ferrucci, Luigi A1 - Gibson, Quince D A1 - Bandinelli, Stefania A1 - Snieder, Harold A1 - Boomsma, Dorret I A1 - Xiao, Xiangjun A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Ridker, Paul M A1 - Homuth, Georg A1 - Koenig, Wolfgang A1 - Ballantyne, Christie M A1 - Witteman, Jacqueline C M A1 - Benjamin, Emelia J A1 - Perola, Markus A1 - Chasman, Daniel I KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Vasculitis AB -

BACKGROUND: 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.

VL - 123 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract ER - TY - JOUR T1 - New gene functions in megakaryopoiesis and platelet formation. JF - Nature Y1 - 2011 A1 - Gieger, Christian A1 - Radhakrishnan, Aparna A1 - Cvejic, Ana A1 - Tang, Weihong A1 - Porcu, Eleonora A1 - Pistis, Giorgio A1 - Serbanovic-Canic, Jovana A1 - Elling, Ulrich A1 - Goodall, Alison H A1 - Labrune, Yann A1 - Lopez, Lorna M A1 - Mägi, Reedik A1 - Meacham, Stuart A1 - Okada, Yukinori A1 - Pirastu, Nicola A1 - Sorice, Rossella A1 - Teumer, Alexander A1 - Voss, Katrin A1 - Zhang, Weihua A1 - Ramirez-Solis, Ramiro A1 - Bis, Joshua C A1 - Ellinghaus, David A1 - Gögele, Martin A1 - Hottenga, Jouke-Jan A1 - Langenberg, Claudia A1 - Kovacs, Peter A1 - O'Reilly, Paul F A1 - Shin, So-Youn A1 - Esko, Tõnu A1 - Hartiala, Jaana A1 - Kanoni, Stavroula A1 - Murgia, Federico A1 - Parsa, Afshin A1 - Stephens, Jonathan A1 - van der Harst, Pim A1 - Ellen van der Schoot, C A1 - Allayee, Hooman A1 - Attwood, Antony A1 - Balkau, Beverley A1 - Bastardot, François A1 - Basu, Saonli A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bomba, Lorenzo A1 - Bonnefond, Amélie A1 - Cambien, Francois A1 - Chambers, John C A1 - Cucca, Francesco A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Boer, Rudolf A A1 - de Geus, Eco J C A1 - Döring, Angela A1 - Elliott, Paul A1 - Erdmann, Jeanette A1 - Evans, David M A1 - Falchi, Mario A1 - Feng, Wei A1 - Folsom, Aaron R A1 - Frazer, Ian H A1 - Gibson, Quince D A1 - Glazer, Nicole L A1 - Hammond, Chris A1 - Hartikainen, Anna-Liisa A1 - Heckbert, Susan R A1 - Hengstenberg, Christian A1 - Hersch, Micha A1 - Illig, Thomas A1 - Loos, Ruth J F A1 - Jolley, Jennifer A1 - Khaw, Kay Tee A1 - Kuhnel, Brigitte A1 - Kyrtsonis, Marie-Christine A1 - Lagou, Vasiliki A1 - Lloyd-Jones, Heather A1 - Lumley, Thomas A1 - Mangino, Massimo A1 - Maschio, Andrea A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Memari, Yasin A1 - Mitchell, Braxton D A1 - Montgomery, Grant W A1 - Nakamura, Yusuke A1 - Nauck, Matthias A1 - Navis, Gerjan A1 - Nöthlings, Ute A1 - Nolte, Ilja M A1 - Porteous, David J A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Pullat, Janne A1 - Ring, Susan M A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ruokonen, Aimo A1 - Sala, Cinzia A1 - Samani, Nilesh J A1 - Sambrook, Jennifer A1 - Schlessinger, David A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Scott, James A1 - Smith, Nicholas L A1 - Snieder, Harold A1 - Starr, John M A1 - Stumvoll, Michael A1 - Takahashi, Atsushi A1 - Tang, W H Wilson A1 - Taylor, Kent A1 - Tenesa, Albert A1 - Lay Thein, Swee A1 - Tönjes, Anke A1 - Uda, Manuela A1 - Ulivi, Sheila A1 - van Veldhuisen, Dirk J A1 - Visscher, Peter M A1 - Völker, Uwe A1 - Wichmann, H-Erich A1 - Wiggins, Kerri L A1 - Willemsen, Gonneke A1 - Yang, Tsun-Po A1 - Hua Zhao, Jing A1 - Zitting, Paavo A1 - Bradley, John R A1 - Dedoussis, George V A1 - Gasparini, Paolo A1 - Hazen, Stanley L A1 - Metspalu, Andres A1 - Pirastu, Mario A1 - Shuldiner, Alan R A1 - Joost van Pelt, L A1 - Zwaginga, Jaap-Jan A1 - Boomsma, Dorret I A1 - Deary, Ian J A1 - Franke, Andre A1 - Froguel, Philippe A1 - Ganesh, Santhi K A1 - Jarvelin, Marjo-Riitta A1 - Martin, Nicholas G A1 - Meisinger, Christa A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Wareham, Nicholas J A1 - Akkerman, Jan-Willem N A1 - Ciullo, Marina A1 - Deloukas, Panos A1 - Greinacher, Andreas A1 - Jupe, Steve A1 - Kamatani, Naoyuki A1 - Khadake, Jyoti A1 - Kooner, Jaspal S A1 - Penninger, Josef A1 - Prokopenko, Inga A1 - Stemple, Derek A1 - Toniolo, Daniela A1 - Wernisch, Lorenz A1 - Sanna, Serena A1 - Hicks, Andrew A A1 - Rendon, Augusto A1 - Ferreira, Manuel A A1 - Ouwehand, Willem H A1 - Soranzo, Nicole KW - Animals KW - Blood Platelets KW - Cell Size KW - Drosophila melanogaster KW - Drosophila Proteins KW - Europe KW - Gene Expression Profiling KW - Gene Silencing KW - Genome, Human KW - Genome-Wide Association Study KW - Hematopoiesis KW - Humans KW - Megakaryocytes KW - Platelet Count KW - Protein Interaction Maps KW - Transcription, Genetic KW - Zebrafish KW - Zebrafish Proteins AB -

Platelets 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.

VL - 480 IS - 7376 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract ER - TY - JOUR T1 - The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. JF - Am J Epidemiol Y1 - 2011 A1 - Matise, Tara C A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Carlson, Christopher S A1 - Cole, Shelley A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Heiss, Gerardo A1 - Kooperberg, Charles A1 - Marchand, Loic Le A1 - Manolio, Teri A A1 - North, Kari E A1 - Peters, Ulrike A1 - Ritchie, Marylyn D A1 - Hindorff, Lucia A A1 - Haines, Jonathan L KW - Epidemiologic Methods KW - Epidemiologic Research Design KW - Ethnic Groups KW - Genetic Association Studies KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Interinstitutional Relations KW - Multifactorial Inheritance KW - National Human Genome Research Institute (U.S.) KW - Phenotype KW - Pilot Projects KW - Research Design KW - Risk Factors KW - United States AB -

Genetic 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.

VL - 174 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21836165?dopt=Abstract ER - TY - JOUR T1 - N-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study. JF - Heart Rhythm Y1 - 2011 A1 - Patton, Kristen K A1 - Sotoodehnia, Nona A1 - DeFilippi, Christopher A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Kronmal, Richard A KW - Age Distribution KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Confidence Intervals KW - Death, Sudden, Cardiac KW - Female KW - Humans KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Assessment KW - Sex Distribution KW - Time Factors KW - United States AB -

BACKGROUND: 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.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21044699?dopt=Abstract ER - TY - JOUR T1 - A phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains. JF - PLoS Genet Y1 - 2011 A1 - Avery, Christy L A1 - He, Qianchuan A1 - North, Kari E A1 - Ambite, José L A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Hindorff, Lucia A A1 - Kooperberg, Charles A1 - Meigs, James B A1 - Pankow, James S A1 - Pendergrass, Sarah A A1 - Psaty, Bruce M A1 - Ritchie, Marylyn D A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Wilkens, Lynne R A1 - Heiss, Gerardo A1 - Lin, Dan Yu KW - African Americans KW - Apolipoprotein C-I KW - Blood Glucose KW - Dyslipidemias KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome, Human KW - Humans KW - Metabolic Syndrome KW - Obesity, Abdominal KW - Phenotype KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable KW - Ubiquitin-Protein Ligases KW - Vascular Diseases AB -

Despite 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.

VL - 7 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22022282?dopt=Abstract ER - TY - JOUR T1 - Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study. JF - Am J Epidemiol Y1 - 2011 A1 - Shoben, Abigail B A1 - Kestenbaum, Bryan A1 - Levin, Gregory A1 - Hoofnagle, Andrew N A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - de Boer, Ian H KW - Aged KW - Biomarkers KW - Continental Population Groups KW - Exercise KW - Female KW - Humans KW - Male KW - Residence Characteristics KW - Seasons KW - Sex Factors KW - Vitamin D AB -

Low 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.

VL - 174 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22112344?dopt=Abstract ER - TY - JOUR T1 - Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. JF - Lancet Y1 - 2011 A1 - Wormser, David A1 - Kaptoge, Stephen A1 - Di Angelantonio, Emanuele A1 - Wood, Angela M A1 - Pennells, Lisa A1 - Thompson, Alex A1 - Sarwar, Nadeem A1 - Kizer, Jorge R A1 - Lawlor, Debbie A A1 - Nordestgaard, Børge G A1 - Ridker, Paul A1 - Salomaa, Veikko A1 - Stevens, June A1 - Woodward, Mark A1 - Sattar, Naveed A1 - Collins, Rory A1 - Thompson, Simon G A1 - Whitlock, Gary A1 - Danesh, John KW - Age Factors KW - Blood Pressure KW - Body Mass Index KW - Cardiovascular Diseases KW - Cholesterol KW - Cholesterol, HDL KW - Diabetes Mellitus KW - Female KW - Humans KW - Male KW - Middle Aged KW - Obesity, Abdominal KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Sex Factors KW - Smoking KW - Systole KW - Waist Circumference KW - Waist-Hip Ratio AB -

BACKGROUND: 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.

VL - 377 IS - 9771 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21397319?dopt=Abstract ER - TY - JOUR T1 - Subclinical vascular disease burden and risk for death and cardiovascular events in older community dwellers. JF - J Gerontol A Biol Sci Med Sci Y1 - 2011 A1 - Inzitari, Marco A1 - Arnold, Alice M A1 - Patel, Kushang V A1 - Mercer, Laina D A1 - Karlamangla, Arun A1 - Ding, Jingzhong A1 - Psaty, Bruce M A1 - Williamson, Jeff D A1 - Kuller, Lewis H A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cost of Illness KW - Female KW - Humans KW - Male KW - Risk KW - Vascular Diseases AB -

BACKGROUND: 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.

VL - 66 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21705627?dopt=Abstract ER - TY - JOUR T1 - Systolic blood pressure and incident heart failure in the elderly. The Cardiovascular Health Study and the Health, Ageing and Body Composition Study. JF - Heart Y1 - 2011 A1 - Butler, Javed A1 - Kalogeropoulos, Andreas P A1 - Georgiopoulou, Vasiliki V A1 - Bibbins-Domingo, Kirsten A1 - Najjar, Samer S A1 - Sutton-Tyrrell, Kim C A1 - Harris, Tamara B A1 - Kritchevsky, Stephen B A1 - Lloyd-Jones, Donald M A1 - Newman, Anne B A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Body Composition KW - Epidemiologic Methods KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Male KW - Myocardial Infarction KW - Sex Factors KW - Stroke KW - Stroke Volume AB -

BACKGROUND: 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.

VL - 97 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21636845?dopt=Abstract ER - TY - JOUR T1 - Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. JF - Diabetes Y1 - 2011 A1 - Kanoni, Stavroula A1 - Nettleton, Jennifer A A1 - Hivert, Marie-France A1 - Ye, Zheng A1 - van Rooij, Frank J A A1 - Shungin, Dmitry A1 - Sonestedt, Emily A1 - Ngwa, Julius S A1 - Wojczynski, Mary K A1 - Lemaitre, Rozenn N A1 - Gustafsson, Stefan A1 - Anderson, Jennifer S A1 - Tanaka, Toshiko A1 - Hindy, George A1 - Saylor, Georgia A1 - Renstrom, Frida A1 - Bennett, Amanda J A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Fox, Caroline S A1 - Hofman, Albert A1 - Hoogeveen, Ron C A1 - Houston, Denise K A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Johansson, Ingegerd A1 - Lind, Lars A1 - Liu, Yongmei A1 - McKeown, Nicola A1 - Ordovas, Jose A1 - Pankow, James S A1 - Sijbrands, Eric J G A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Wareham, Nick J A1 - Prokopenko, Inga A1 - Bandinelli, Stefania A1 - Forouhi, Nita G A1 - Cupples, L Adrienne A1 - Loos, Ruth J A1 - Hallmans, Göran A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Ferrucci, Luigi A1 - Kritchevsky, Stephen B A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Borecki, Ingrid B A1 - Witteman, Jacqueline C M A1 - Orho-Melander, Marju A1 - Siscovick, David S A1 - Meigs, James B A1 - Franks, Paul W A1 - Dedoussis, George V KW - Blood Glucose KW - Cation Transport Proteins KW - Cohort Studies KW - Humans KW - Polymorphism, Single Nucleotide KW - Zinc KW - Zinc Transporter 8 AB -

OBJECTIVE: 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.

VL - 60 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21810599?dopt=Abstract ER - TY - JOUR T1 - Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study. JF - Hypertension Y1 - 2011 A1 - Deo, Rajat A1 - Katz, Ronit A1 - Shlipak, Michael G A1 - Sotoodehnia, Nona A1 - Psaty, Bruce M A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Chonchol, Michel A1 - de Boer, Ian H A1 - Enquobahrie, Daniel A1 - Siscovick, David A1 - Kestenbaum, Bryan KW - Aged KW - Cardiovascular Diseases KW - Comorbidity KW - Death, Sudden, Cardiac KW - Diabetes Mellitus KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Incidence KW - Kidney KW - Male KW - Middle Aged KW - Minerals KW - Parathyroid Hormone KW - Proportional Hazards Models KW - Risk Factors KW - Socioeconomic Factors KW - United States KW - Vitamin D AB -

Recent 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.

VL - 58 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22068871?dopt=Abstract ER - TY - JOUR T1 - Assessment of gene-by-sex interaction effect on bone mineral density. JF - J Bone Miner Res Y1 - 2012 A1 - Liu, Ching-Ti A1 - Estrada, Karol A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Evangelou, Evangelos A1 - Li, Guo A1 - Minster, Ryan L A1 - Carless, Melanie A A1 - Kammerer, Candace M A1 - Oei, Ling A1 - Zhou, Yanhua A1 - Alonso, Nerea A1 - Dailiana, Zoe A1 - Eriksson, Joel A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Husted, Lise Bjerre A1 - Khusainova, Rita I A1 - Koromila, Theodora A1 - Kung, Annie Waichee A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Richards, J Brent A1 - Sham, Pak Chung A1 - Spector, Timothy A1 - Vandenput, Liesbeth A1 - Xiao, Su-Mei A1 - Zheng, Hou-Feng A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza K A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Marc, Janja A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Olmos, José M A1 - Ralston, Stuart H A1 - Riancho, José A A1 - Rousseau, François A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Zarrabeitia, María T A1 - Castano-Betancourt, Martha A1 - Demissie, Serkalem A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Kwan, Tony A1 - Medina-Gómez, Carolina A1 - Pastinen, Tomi A1 - Sigurdsson, Gunnar A1 - Thorleifsson, Gudmar A1 - Vanmeurs, Joyce Bj A1 - Blangero, John A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Mitchell, Braxton D A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Rotter, Jerome I A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Thorsteinsdottir, Unnur A1 - Tylavsky, Frances A A1 - Uitterlinden, Andre A1 - Cauley, Jane A A1 - Harris, Tamara B A1 - Ioannidis, John Pa A1 - Psaty, Bruce M A1 - Robbins, John A A1 - Zillikens, M Carola A1 - Vanduijn, Cornelia M A1 - Prince, Richard L A1 - Karasik, David A1 - Rivadeneira, Fernando A1 - Kiel, Douglas P A1 - Cupples, L Adrienne A1 - Hsu, Yi-Hsiang KW - Bone Density KW - Cohort Studies KW - Female KW - Genes KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Sex Characteristics AB -

Sexual 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.

VL - 27 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract ER - TY - JOUR T1 - Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Murabito, Joanne M A1 - White, Charles C A1 - Kavousi, Maryam A1 - Sun, Yan V A1 - Feitosa, Mary F A1 - Nambi, Vijay A1 - Lamina, Claudia A1 - Schillert, Arne A1 - Coassin, Stefan A1 - Bis, Joshua C A1 - Broer, Linda A1 - Crawford, Dana C A1 - Franceschini, Nora A1 - Frikke-Schmidt, Ruth A1 - Haun, Margot A1 - Holewijn, Suzanne A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Kiechl, Stefan A1 - Kollerits, Barbara A1 - Montasser, May E A1 - Nolte, Ilja M A1 - Rudock, Megan E A1 - Senft, Andrea A1 - Teumer, Alexander A1 - van der Harst, Pim A1 - Vitart, Veronique A1 - Waite, Lindsay L A1 - Wood, Andrew R A1 - Wassel, Christina L A1 - Absher, Devin M A1 - Allison, Matthew A A1 - Amin, Najaf A1 - Arnold, Alice A1 - Asselbergs, Folkert W A1 - Aulchenko, Yurii A1 - Bandinelli, Stefania A1 - Barbalic, Maja A1 - Boban, Mladen A1 - Brown-Gentry, Kristin A1 - Couper, David J A1 - Criqui, Michael H A1 - Dehghan, Abbas A1 - den Heijer, Martin A1 - Dieplinger, Benjamin A1 - Ding, Jingzhong A1 - Dörr, Marcus A1 - Espinola-Klein, Christine A1 - Felix, Stephan B A1 - Ferrucci, Luigi A1 - Folsom, Aaron R A1 - Fraedrich, Gustav A1 - Gibson, Quince A1 - Goodloe, Robert A1 - Gunjaca, Grgo A1 - Haltmayer, Meinhard A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Kieback, Arne A1 - Kiemeney, Lambertus A A1 - Kolcic, Ivana A1 - Kullo, Iftikhar J A1 - Kritchevsky, Stephen B A1 - Lackner, Karl J A1 - Li, Xiaohui A1 - Lieb, Wolfgang A1 - Lohman, Kurt A1 - Meisinger, Christa A1 - Melzer, David A1 - Mohler, Emile R A1 - Mudnic, Ivana A1 - Mueller, Thomas A1 - Navis, Gerjan A1 - Oberhollenzer, Friedrich A1 - Olin, Jeffrey W A1 - O'Connell, Jeff A1 - O'Donnell, Christopher J A1 - Palmas, Walter A1 - Penninx, Brenda W A1 - Petersmann, Astrid A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Rantner, Barbara A1 - Rice, Ken A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seldenrijk, Adrie A1 - Stadler, Marietta A1 - Summerer, Monika A1 - Tanaka, Toshiko A1 - Tybjaerg-Hansen, Anne A1 - Uitterlinden, André G A1 - van Gilst, Wiek H A1 - Vermeulen, Sita H A1 - Wild, Sarah H A1 - Wild, Philipp S A1 - Willeit, Johann A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Assimes, Themistocles L A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Campbell, Harry A1 - Cooke, John P A1 - de Graaf, Jacqueline A1 - Herrington, David A1 - Kardia, Sharon L R A1 - Mitchell, Braxton D A1 - Murray, Anna A1 - Münzel, Thomas A1 - Newman, Anne B A1 - Oostra, Ben A A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Snieder, Harold A1 - van Duijn, Cornelia M A1 - Völker, Uwe A1 - Wright, Alan F A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Liu, Yongmei A1 - Hayward, Caroline A1 - Borecki, Ingrid B A1 - Ziegler, Andreas A1 - North, Kari E A1 - Cupples, L Adrienne A1 - Kronenberg, Florian KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Ankle Brachial Index KW - Chromosomes, Human, Pair 9 KW - Cohort Studies KW - Cyclin-Dependent Kinase Inhibitor p15 KW - Female KW - Genome-Wide Association Study KW - Genotype KW - HapMap Project KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Peripheral Vascular Diseases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sex Factors AB -

BACKGROUND: 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.

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract ER - TY - JOUR T1 - Association of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe). JF - PLoS One Y1 - 2012 A1 - Patel, Sanjay R A1 - Goodloe, Robert A1 - De, Gourab A1 - Kowgier, Matthew A1 - Weng, Jia A1 - Buxbaum, Sarah G A1 - Cade, Brian A1 - Fulop, Tibor A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Hillman, David A1 - Larkin, Emma K A1 - Lauderdale, Diane S A1 - Li, Li A1 - Mukherjee, Sutapa A1 - Palmer, Lyle A1 - Zee, Phyllis A1 - Zhu, Xiaofeng A1 - Redline, Susan KW - Adult KW - African Americans KW - Aged KW - Alleles KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Polysomnography KW - Sleep Apnea, Obstructive AB -

Although 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.

VL - 7 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23155414?dopt=Abstract ER - TY - JOUR T1 - Association of weight status with mortality in adults with incident diabetes. JF - JAMA Y1 - 2012 A1 - Carnethon, Mercedes R A1 - De Chavez, Peter John D A1 - Biggs, Mary L A1 - Lewis, Cora E A1 - Pankow, James S A1 - Bertoni, Alain G A1 - Golden, Sherita H A1 - Liu, Kiang A1 - Mukamal, Kenneth J A1 - Campbell-Jenkins, Brenda A1 - Dyer, Alan R KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Body Weight KW - Cardiovascular Diseases KW - Cause of Death KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Obesity KW - Overweight KW - United States AB -

CONTEXT: 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.

VL - 308 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22871870?dopt=Abstract ER - TY - JOUR T1 - Associations 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. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Carty, Cara L A1 - Bůzková, Petra A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Cole, Shelley A1 - Heiss, Gerardo A1 - Hindorff, Lucia A A1 - Howard, Barbara V A1 - Mann, Sue A1 - Martin, Lisa W A1 - Zhang, Ying A1 - Matise, Tara C A1 - Prentice, Ross A1 - Reiner, Alexander P A1 - Kooperberg, Charles KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Female KW - Genetics, Population KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Triglycerides AB -

BACKGROUND: 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.

VL - 5 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22403240?dopt=Abstract ER - TY - JOUR T1 - Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. JF - Lancet Y1 - 2012 A1 - Fox, Caroline S A1 - Matsushita, Kunihiro A1 - Woodward, Mark A1 - Bilo, Henk J G A1 - Chalmers, John A1 - Heerspink, Hiddo J Lambers A1 - Lee, Brian J A1 - Perkins, Robert M A1 - Rossing, Peter A1 - Sairenchi, Toshimi A1 - Tonelli, Marcello A1 - Vassalotti, Joseph A A1 - Yamagishi, Kazumasa A1 - Coresh, Josef A1 - de Jong, Paul E A1 - Wen, Chi-Pang A1 - Nelson, Robert G KW - Aged KW - Albuminuria KW - Cardiovascular Diseases KW - Cause of Death KW - Diabetic Nephropathies KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: 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.

VL - 380 IS - 9854 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23013602?dopt=Abstract ER - TY - JOUR T1 - Bootstrap-based inference on the difference in the means of two correlated functional processes. JF - Stat Med Y1 - 2012 A1 - Crainiceanu, Ciprian M A1 - Staicu, Ana-Maria A1 - Ray, Shubankar A1 - Punjabi, Naresh KW - Biostatistics KW - Cohort Studies KW - Confidence Intervals KW - Humans KW - Models, Statistical KW - Sleep Apnea Syndromes KW - Statistics, Nonparametric AB -

We 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.

VL - 31 IS - 26 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22855258?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular physiology in premotor Parkinson's disease: a neuroepidemiologic study. JF - Mov Disord Y1 - 2012 A1 - Jain, Samay A1 - Ton, Thanh G A1 - Perera, Subashan A1 - Zheng, Yan A1 - Stein, Phyllis K A1 - Thacker, Evan A1 - Strotmeyer, Elsa S A1 - Newman, Anne B A1 - Longstreth, Will T KW - Aged KW - Antiparkinson Agents KW - Cardiovascular Physiological Phenomena KW - Carotid Stenosis KW - Cohort Studies KW - Data Interpretation, Statistical KW - Dizziness KW - Electrocardiography KW - Female KW - Heart Rate KW - Hospitalization KW - Humans KW - Longitudinal Studies KW - Male KW - Movement Disorders KW - Neurologic Examination KW - Parkinson Disease KW - Risk KW - Ultrasonography AB -

Changes 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.

VL - 27 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22700356?dopt=Abstract ER - TY - JOUR T1 - Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. JF - Lancet Y1 - 2012 A1 - Lorenz, Matthias W A1 - Polak, Joseph F A1 - Kavousi, Maryam A1 - Mathiesen, Ellisiv B A1 - Völzke, Henry A1 - Tuomainen, Tomi-Pekka A1 - Sander, Dirk A1 - Plichart, Matthieu A1 - Catapano, Alberico L A1 - Robertson, Christine M A1 - Kiechl, Stefan A1 - Rundek, Tatjana A1 - Desvarieux, Moïse A1 - Lind, Lars A1 - Schmid, Caroline A1 - DasMahapatra, Pronabesh A1 - Gao, Lu A1 - Ziegelbauer, Kathrin A1 - Bots, Michiel L A1 - Thompson, Simon G KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Disease Progression KW - Follow-Up Studies KW - Humans KW - Myocardial Infarction KW - Prognosis KW - Risk Assessment KW - Stroke AB -

BACKGROUND: 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.

VL - 379 IS - 9831 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22541275?dopt=Abstract ER - TY - JOUR T1 - Chronic kidney disease, insulin resistance, and incident diabetes in older adults. JF - Clin J Am Soc Nephrol Y1 - 2012 A1 - Pham, Hien A1 - Robinson-Cohen, Cassianne A1 - Biggs, Mary L A1 - Ix, Joachim H A1 - Mukamal, Kenneth J A1 - Fried, Linda F A1 - Kestenbaum, Bryan A1 - Siscovick, David S A1 - de Boer, Ian H KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Chronic Disease KW - Creatinine KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Glucose Tolerance Test KW - Health Surveys KW - Humans KW - Hypoglycemic Agents KW - Incidence KW - Insulin KW - Insulin Resistance KW - Insulin-Secreting Cells KW - Kidney KW - Kidney Diseases KW - Linear Models KW - Male KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - United States AB -

BACKGROUND 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.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22383749?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. JF - Diabetologia Y1 - 2012 A1 - Walford, G A A1 - Green, T A1 - Neale, B A1 - Isakova, T A1 - Rotter, J I A1 - Grant, S F A A1 - Fox, C S A1 - Pankow, J S A1 - Wilson, J G A1 - Meigs, J B A1 - Siscovick, D S A1 - Bowden, D W A1 - Daly, M J A1 - Florez, J C KW - Adult KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Disease Progression KW - Fasting KW - Female KW - Genetic Variation KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Regression Analysis KW - Risk AB -

AIMS/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.

VL - 55 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22038522?dopt=Abstract ER - TY - JOUR T1 - Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JF - JAMA Y1 - 2012 A1 - Matsushita, Kunihiro A1 - Mahmoodi, Bakhtawar K A1 - Woodward, Mark A1 - Emberson, Jonathan R A1 - Jafar, Tazeen H A1 - Jee, Sun Ha A1 - Polkinghorne, Kevan R A1 - Shankar, Anoop A1 - Smith, David H A1 - Tonelli, Marcello A1 - Warnock, David G A1 - Wen, Chi-Pang A1 - Coresh, Josef A1 - Gansevoort, Ron T A1 - Hemmelgarn, Brenda R A1 - Levey, Andrew S KW - African Continental Ancestry Group KW - Aged KW - Algorithms KW - Asian Continental Ancestry Group KW - Cardiovascular Diseases KW - Cohort Studies KW - Decision Support Techniques KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Models, Theoretical KW - Risk Assessment KW - Sex Factors AB -

CONTEXT: 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.

VL - 307 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22570462?dopt=Abstract ER - TY - JOUR T1 - Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. JF - Diabetes Y1 - 2012 A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Spencer, Kylee L A1 - Bůzková, Petra A1 - Voruganti, V Saroja A1 - Wan, Peggy A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Monroe, Kristine R A1 - Howard, Barbara V A1 - Jackson, Rebecca D A1 - Florez, Jose C A1 - Kolonel, Laurence N A1 - Buyske, Steven A1 - Goodloe, Robert J A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Meigs, James B A1 - Waters, Kevin A1 - Mukamal, Kenneth J A1 - Pendergrass, Sarah A A1 - Shrader, Peter A1 - Wilkens, Lynne R A1 - Hindorff, Lucia A A1 - Ambite, Jose Luis A1 - North, Kari E A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - Le Marchand, Loïc A1 - Pankow, James S KW - Adult KW - Aged KW - Aged, 80 and over KW - Alleles KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Metagenomics KW - Middle Aged KW - Population Groups KW - Risk KW - Risk Factors AB -

Common 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.

VL - 61 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract ER - TY - JOUR T1 - Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study. JF - J Clin Endocrinol Metab Y1 - 2012 A1 - Kaplan, Robert C A1 - Bůzková, Petra A1 - Cappola, Anne R A1 - Strickler, Howard D A1 - McGinn, Aileen P A1 - Mercer, Laina D A1 - Arnold, Alice M A1 - Pollak, Michael N A1 - Newman, Anne B KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Longitudinal Studies KW - Male KW - Mortality KW - Predictive Value of Tests KW - Risk Factors AB -

BACKGROUND: 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.

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22442270?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a coronary risk prediction model for older U.S. and European persons in the Cardiovascular Health Study and the Rotterdam Study. JF - Ann Intern Med Y1 - 2012 A1 - Koller, Michael T A1 - Leening, Maarten J G A1 - Wolbers, Marcel A1 - Steyerberg, Ewout W A1 - Hunink, M G Myriam A1 - Schoop, Rotraut A1 - Hofman, Albert A1 - Bucher, Heiner C A1 - Psaty, Bruce M A1 - Lloyd-Jones, Donald M A1 - Witteman, Jacqueline C M KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Cause of Death KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Male KW - Models, Statistical KW - Multivariate Analysis KW - Netherlands KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - United States AB -

BACKGROUND: 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.

VL - 157 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22986376?dopt=Abstract ER - TY - JOUR T1 - Eight 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. JF - Eur Heart J Y1 - 2012 A1 - Grallert, Harald A1 - Dupuis, Josée A1 - Bis, Joshua C A1 - Dehghan, Abbas A1 - Barbalic, Maja A1 - Baumert, Jens A1 - Lu, Chen A1 - Smith, Nicholas L A1 - Uitterlinden, André G A1 - Roberts, Robert A1 - Khuseyinova, Natalie A1 - Schnabel, Renate B A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Hoogeveen, Ron C A1 - Fontes, João Daniel A1 - Meisinger, Christa A1 - Keaney, John F A1 - Lemaitre, Rozenn A1 - Aulchenko, Yurii S A1 - Vasan, Ramachandran S A1 - Ellis, Stephen A1 - Hazen, Stanley L A1 - van Duijn, Cornelia M A1 - Nelson, Jeanenne J A1 - März, Winfried A1 - Schunkert, Heribert A1 - McPherson, Ruth M A1 - Stirnadel-Farrant, Heide A A1 - Psaty, Bruce M A1 - Gieger, Christian A1 - Siscovick, David A1 - Hofman, Albert A1 - Illig, Thomas A1 - Cushman, Mary A1 - Yamamoto, Jennifer F A1 - Rotter, Jerome I A1 - Larson, Martin G A1 - Stewart, Alexandre F R A1 - Boerwinkle, Eric A1 - Witteman, Jacqueline C M A1 - Tracy, Russell P A1 - Koenig, Wolfgang A1 - Benjamin, Emelia J A1 - Ballantyne, Christie M KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Coronary Artery Disease KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Phospholipases A2 KW - Polymorphism, Single Nucleotide AB -

AIMS: 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.

VL - 33 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22003152?dopt=Abstract ER - TY - JOUR T1 - Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. JF - PLoS One Y1 - 2012 A1 - Buyske, Steven A1 - Wu, Ying A1 - Carty, Cara L A1 - Cheng, Iona A1 - Assimes, Themistocles L A1 - Dumitrescu, Logan A1 - Hindorff, Lucia A A1 - Mitchell, Sabrina A1 - Ambite, Jose Luis A1 - Boerwinkle, Eric A1 - Bůzková, Petra A1 - Carlson, Chris S A1 - Cochran, Barbara A1 - Duggan, David A1 - Eaton, Charles B A1 - Fesinmeyer, Megan D A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Jenny, Nancy A1 - Kang, Hyun Min A1 - Kooperberg, Charles A1 - Lin, Yi A1 - Le Marchand, Loïc A1 - Matise, Tara C A1 - Robinson, Jennifer G A1 - Rodriguez, Carlos A1 - Schumacher, Fredrick R A1 - Voight, Benjamin F A1 - Young, Alicia A1 - Manolio, Teri A A1 - Mohlke, Karen L A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - North, Kari E KW - African Americans KW - Cardiovascular Diseases KW - Cholesterol Ester Transfer Proteins KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Chromosomes, Human KW - Cohort Studies KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Metabolic Diseases KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

The 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.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping and initial characterization of QT interval loci in African Americans. JF - PLoS Genet Y1 - 2012 A1 - Avery, Christy L A1 - Sethupathy, Praveen A1 - Buyske, Steven A1 - He, Qianchuan A1 - Lin, Dan-Yu A1 - Arking, Dan E A1 - Carty, Cara L A1 - Duggan, David A1 - Fesinmeyer, Megan D A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Klein, Liviu A1 - Patton, Kristen K A1 - Peters, Ulrike A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Young, Alicia M A1 - Kooperberg, Charles A1 - Haiman, Christopher A A1 - Mohlke, Karen L A1 - Whitsel, Eric A A1 - North, Kari E KW - African Americans KW - Aged KW - Computational Biology KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors KW - Tachycardia KW - United States AB -

The 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.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract ER - TY - JOUR T1 - FTO genotype is associated with phenotypic variability of body mass index. JF - Nature Y1 - 2012 A1 - Yang, Jian A1 - Loos, Ruth J F A1 - Powell, Joseph E A1 - Medland, Sarah E A1 - Speliotes, Elizabeth K A1 - Chasman, Daniel I A1 - Rose, Lynda M A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Mägi, Reedik A1 - Waite, Lindsay A1 - Smith, Albert Vernon A1 - Yerges-Armstrong, Laura M A1 - Monda, Keri L A1 - Hadley, David A1 - Mahajan, Anubha A1 - Li, Guo A1 - Kapur, Karen A1 - Vitart, Veronique A1 - Huffman, Jennifer E A1 - Wang, Sophie R A1 - Palmer, Cameron A1 - Esko, Tõnu A1 - Fischer, Krista A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Feitosa, Mary F A1 - Luan, Jian'an A1 - Heard-Costa, Nancy L A1 - White, Charles A1 - Jackson, Anne U A1 - Preuss, Michael A1 - Ziegler, Andreas A1 - Eriksson, Joel A1 - Kutalik, Zoltán A1 - Frau, Francesca A1 - Nolte, Ilja M A1 - van Vliet-Ostaptchouk, Jana V A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Verweij, Niek A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Estrada, Karol A1 - Bragg-Gresham, Jennifer Lynn A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Prokopenko, Inga A1 - Mangino, Massimo A1 - Lindgren, Cecilia M A1 - Assimes, Themistocles L A1 - Shuldiner, Alan R A1 - Hui, Jennie A1 - Beilby, John P A1 - McArdle, Wendy L A1 - Hall, Per A1 - Haritunians, Talin A1 - Zgaga, Lina A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Oostra, Ben A A1 - Junttila, M Juhani A1 - Grönberg, Henrik A1 - Schreiber, Stefan A1 - Peters, Annette A1 - Hicks, Andrew A A1 - Stephens, Jonathan A1 - Foad, Nicola S A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Kaakinen, Marika A1 - Willemsen, Gonneke A1 - Vink, Jacqueline M A1 - Wild, Sarah H A1 - Navis, Gerjan A1 - Asselbergs, Folkert W A1 - Homuth, Georg A1 - John, Ulrich A1 - Iribarren, Carlos A1 - Harris, Tamara A1 - Launer, Lenore A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Boerwinkle, Eric A1 - Cadby, Gemma A1 - Palmer, Lyle J A1 - James, Alan L A1 - Musk, Arthur W A1 - Ingelsson, Erik A1 - Psaty, Bruce M A1 - Beckmann, Jacques S A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Hayward, Caroline A1 - Wright, Alan F A1 - Rudan, Igor A1 - Groop, Leif C A1 - Metspalu, Andres A1 - Khaw, Kay Tee A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Province, Michael A A1 - Wareham, Nicholas J A1 - Tardif, Jean-Claude A1 - Huikuri, Heikki V A1 - Cupples, L Adrienne A1 - Atwood, Larry D A1 - Fox, Caroline S A1 - Boehnke, Michael A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Erdmann, Jeanette A1 - Schunkert, Heribert A1 - Hengstenberg, Christian A1 - Stark, Klaus A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Cusi, Daniele A1 - Staessen, Jan A A1 - van der Klauw, Melanie M A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Jolley, Jennifer D A1 - Ripatti, Samuli A1 - Jarvelin, Marjo-Riitta A1 - de Geus, Eco J C A1 - Boomsma, Dorret I A1 - Penninx, Brenda A1 - Wilson, James F A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Hofman, Albert A1 - Witteman, Jacqueline C A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Zillikens, M Carola A1 - Kiemeney, Lambertus A A1 - Vermeulen, Sita H A1 - Abecasis, Goncalo R A1 - Schlessinger, David A1 - Schipf, Sabine A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Spector, Tim D A1 - North, Kari E A1 - Lettre, Guillaume A1 - McCarthy, Mark I A1 - Berndt, Sonja I A1 - Heath, Andrew C A1 - Madden, Pamela A F A1 - Nyholt, Dale R A1 - Montgomery, Grant W A1 - Martin, Nicholas G A1 - McKnight, Barbara A1 - Strachan, David P A1 - Hill, William G A1 - Snieder, Harold A1 - Ridker, Paul M A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Goddard, Michael E A1 - Visscher, Peter M KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Body Height KW - Body Mass Index KW - Co-Repressor Proteins KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proteins KW - Repressor Proteins AB -

There 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.

VL - 490 IS - 7419 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22982992?dopt=Abstract ER - TY - JOUR T1 - Genetic 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. JF - Atherosclerosis Y1 - 2012 A1 - Wassel, Christina L A1 - Lamina, Claudia A1 - Nambi, Vijay A1 - Coassin, Stefan A1 - Mukamal, Kenneth J A1 - Ganesh, Santhi K A1 - Jacobs, David R A1 - Franceschini, Nora A1 - Papanicolaou, George J A1 - Gibson, Quince A1 - Yanek, Lisa R A1 - van der Harst, Pim A1 - Ferguson, Jane F A1 - Crawford, Dana C A1 - Waite, Lindsay L A1 - Allison, Matthew A A1 - Criqui, Michael H A1 - McDermott, Mary M A1 - Mehra, Reena A1 - Cupples, L Adrienne A1 - Hwang, Shih-Jen A1 - Redline, Susan A1 - Kaplan, Robert C A1 - Heiss, Gerardo A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Taylor, Herman A A1 - Eraso, Luis H A1 - Haun, Margot A1 - Li, Mingyao A1 - Meisinger, Christa A1 - O'Connell, Jeffrey R A1 - Shuldiner, Alan R A1 - Tybjærg-Hansen, Anne A1 - Frikke-Schmidt, Ruth A1 - Kollerits, Barbara A1 - Rantner, Barbara A1 - Dieplinger, Benjamin A1 - Stadler, Marietta A1 - Mueller, Thomas A1 - Haltmayer, Meinhard A1 - Klein-Weigel, Peter A1 - Summerer, Monika A1 - Wichmann, H-Erich A1 - Asselbergs, Folkert W A1 - Navis, Gerjan A1 - Mateo Leach, Irene A1 - Brown-Gentry, Kristin A1 - Goodloe, Robert A1 - Assimes, Themistocles L A1 - Becker, Diane M A1 - Cooke, John P A1 - Absher, Devin M A1 - Olin, Jeffrey W A1 - Mitchell, Braxton D A1 - Reilly, Muredach P A1 - Mohler, Emile R A1 - North, Kari E A1 - Reiner, Alexander P A1 - Kronenberg, Florian A1 - Murabito, Joanne M KW - Adult KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Aryl Hydrocarbon Hydroxylases KW - Cytochrome P-450 CYP2B6 KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Oxidoreductases, N-Demethylating KW - Peripheral Arterial Disease KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: 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.

VL - 222 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22361517?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

BACKGROUND: 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).

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JF - JAMA Y1 - 2012 A1 - Levin, Gregory P A1 - Robinson-Cohen, Cassianne A1 - de Boer, Ian H A1 - Houston, Denise K A1 - Lohman, Kurt A1 - Liu, Yongmei A1 - Kritchevsky, Stephen B A1 - Cauley, Jane A A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Patel, Kushang V A1 - Hagström, Emil A1 - Michaëlsson, Karl A1 - Melhus, Håkan A1 - Wang, Thomas A1 - Wolf, Myles A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Kestenbaum, Bryan KW - 25-Hydroxyvitamin D3 1-alpha-Hydroxylase KW - Aged KW - Chronic Disease KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genotype KW - Hip Fractures KW - Humans KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Male KW - Meta-Analysis as Topic KW - Myocardial Infarction KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Receptors, Calcitriol KW - Receptors, Cell Surface KW - Risk KW - Steroid Hydroxylases KW - Vitamin D KW - Vitamin D3 24-Hydroxylase AB -

CONTEXT: 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.

VL - 308 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23150009?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic 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.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. JF - Am J Respir Crit Care Med Y1 - 2012 A1 - Wilk, Jemma B A1 - Shrine, Nick R G A1 - Loehr, Laura R A1 - Zhao, Jing Hua A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Smith, Albert Vernon A1 - Heckbert, Susan R A1 - Smolonska, Joanna A1 - Tang, Wenbo A1 - Loth, Daan W A1 - Curjuric, Ivan A1 - Hui, Jennie A1 - Cho, Michael H A1 - Latourelle, Jeanne C A1 - Henry, Amanda P A1 - Aldrich, Melinda A1 - Bakke, Per A1 - Beaty, Terri H A1 - Bentley, Amy R A1 - Borecki, Ingrid B A1 - Brusselle, Guy G A1 - Burkart, Kristin M A1 - Chen, Ting-Hsu A1 - Couper, David A1 - Crapo, James D A1 - Davies, Gail A1 - Dupuis, Josée A1 - Franceschini, Nora A1 - Gulsvik, Amund A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Imboden, Medea A1 - James, Alan L A1 - Khaw, Kay-Tee A1 - Lahousse, Lies A1 - Launer, Lenore J A1 - Litonjua, Augusto A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Lomas, David A A1 - Lumley, Thomas A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - Musk, Arthur W A1 - Myers, Richard H A1 - North, Kari E A1 - Postma, Dirkje S A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Rotter, Jerome I A1 - Soler Artigas, Maria A1 - Starr, John M A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Zanen, Pieter A1 - Province, Michael A A1 - Silverman, Edwin K A1 - Deary, Ian J A1 - Palmer, Lyle J A1 - Cassano, Patricia A A1 - Gudnason, Vilmundur A1 - Barr, R Graham A1 - Loos, Ruth J F A1 - Strachan, David P A1 - London, Stephanie J A1 - Boezen, H Marike A1 - Probst-Hensch, Nicole A1 - Gharib, Sina A A1 - Hall, Ian P A1 - O'Connor, George T A1 - Tobin, Martin D A1 - Stricker, Bruno H KW - Aged KW - Female KW - Forced Expiratory Volume KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Nicotinic KW - Receptors, Serotonin, 5-HT4 KW - Smoking KW - Vital Capacity AB -

RATIONALE: 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.

VL - 186 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. JF - Blood Y1 - 2012 A1 - Huang, Jie A1 - Sabater-Lleal, Maria A1 - Asselbergs, Folkert W A1 - Tregouet, David A1 - Shin, So-Youn A1 - Ding, Jingzhong A1 - Baumert, Jens A1 - Oudot-Mellakh, Tiphaine A1 - Folkersen, Lasse A1 - Johnson, Andrew D A1 - Smith, Nicholas L A1 - Williams, Scott M A1 - Ikram, Mohammad A A1 - Kleber, Marcus E A1 - Becker, Diane M A1 - Truong, Vinh A1 - Mychaleckyj, Josyf C A1 - Tang, Weihong A1 - Yang, Qiong A1 - Sennblad, Bengt A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Dehghan, Abbas A1 - Silbernagel, Günther A1 - Schrijvers, Elisabeth M C A1 - Smith, Shelly A1 - Karakas, Mahir A1 - Tofler, Geoffrey H A1 - Silveira, Angela A1 - Navis, Gerjan J A1 - Lohman, Kurt A1 - Chen, Ming-Huei A1 - Peters, Annette A1 - Goel, Anuj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Lundmark, Per A1 - Psaty, Bruce M A1 - Strawbridge, Rona J A1 - Boehm, Bernhard O A1 - Carter, Angela M A1 - Meisinger, Christa A1 - Peden, John F A1 - Bis, Joshua C A1 - McKnight, Barbara A1 - Ohrvik, John A1 - Taylor, Kent A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Collins, Rory A1 - Franco-Cereceda, Anders A1 - Syvänen, Ann-Christine A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Cushman, Mary A1 - Müller-Nurasyid, Martina A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Kooner, Jaspal S A1 - Hofman, Albert A1 - Danesh, John A1 - Clarke, Robert A1 - Meigs, James B A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Klopp, Norman A1 - Harris, Tamara B A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Watkins, Hugh A1 - Spector, Timothy D A1 - Becker, Lewis C A1 - Tracy, Russell P A1 - März, Winfried A1 - Uitterlinden, André G A1 - Eriksson, Per A1 - Cambien, Francois A1 - Morange, Pierre-Emmanuel A1 - Koenig, Wolfgang A1 - Soranzo, Nicole A1 - van der Harst, Pim A1 - Liu, Yongmei A1 - O'Donnell, Christopher J A1 - Hamsten, Anders KW - Adaptor Proteins, Signal Transducing KW - ARNTL Transcription Factors KW - ATPases Associated with Diverse Cellular Activities KW - Cell Line KW - Cell Line, Tumor KW - Cohort Studies KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - LIM Domain Proteins KW - Meta-Analysis as Topic KW - Monocytes KW - Mucin-3 KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - PPAR gamma KW - Proteasome Endopeptidase Complex KW - RNA Interference KW - Transcription Factors AB -

We 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.

VL - 120 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract ER - TY - JOUR T1 - Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. JF - PLoS Genet Y1 - 2012 A1 - Hancock, Dana B A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Henry, Amanda A1 - Manichaikul, Ani A1 - Ramasamy, Adaikalavan A1 - Loth, Daan W A1 - Imboden, Medea A1 - Koch, Beate A1 - McArdle, Wendy L A1 - Smith, Albert V A1 - Smolonska, Joanna A1 - Sood, Akshay A1 - Tang, Wenbo A1 - Wilk, Jemma B A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Aschard, Hugues A1 - Burkart, Kristin M A1 - Curjuric, Ivan A1 - Eijgelsheim, Mark A1 - Elliott, Paul A1 - Gu, Xiangjun A1 - Harris, Tamara B A1 - Janson, Christer A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - Liu, Jason Z A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Manning, Alisa K A1 - Marciante, Kristin D A1 - Obeidat, Ma'en A1 - Postma, Dirkje S A1 - Aldrich, Melinda C A1 - Brusselle, Guy G A1 - Chen, Ting-Hsu A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Heinrich, Joachim A1 - Rotter, Jerome I A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Bentley, Amy R A1 - Hofman, Albert A1 - Laurie, Cathy C A1 - Lumley, Thomas A1 - Morrison, Alanna C A1 - Joubert, Bonnie R A1 - Rivadeneira, Fernando A1 - Couper, David J A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Wjst, Matthias A1 - Wain, Louise V A1 - Vonk, Judith M A1 - Uitterlinden, André G A1 - Rochat, Thierry A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - O'Connor, George T A1 - North, Kari E A1 - Mirel, Daniel B A1 - Meibohm, Bernd A1 - Launer, Lenore J A1 - Khaw, Kay-Tee A1 - Hartikainen, Anna-Liisa A1 - Hammond, Christopher J A1 - Gläser, Sven A1 - Marchini, Jonathan A1 - Kraft, Peter A1 - Wareham, Nicholas J A1 - Völzke, Henry A1 - Stricker, Bruno H C A1 - Spector, Timothy D A1 - Probst-Hensch, Nicole M A1 - Jarvis, Deborah A1 - Jarvelin, Marjo-Riitta A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Boezen, H Marike A1 - Barr, R Graham A1 - Cassano, Patricia A A1 - Strachan, David P A1 - Fornage, Myriam A1 - Hall, Ian P A1 - Dupuis, Josée A1 - Tobin, Martin D A1 - London, Stephanie J KW - Forced Expiratory Volume KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - HLA-DQ Antigens KW - HLA-DQ beta-Chains KW - Humans KW - Lung KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Inwardly Rectifying KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Cell Surface KW - Smoking KW - SOX9 Transcription Factor KW - Vital Capacity AB -

Genome-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.

VL - 8 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analyses of smoking behaviors in African Americans. JF - Transl Psychiatry Y1 - 2012 A1 - David, S P A1 - Hamidovic, A A1 - Chen, G K A1 - Bergen, A W A1 - Wessel, J A1 - Kasberger, J L A1 - Brown, W M A1 - Petruzella, S A1 - Thacker, E L A1 - Kim, Y A1 - Nalls, M A A1 - Tranah, G J A1 - Sung, Y J A1 - Ambrosone, C B A1 - Arnett, D A1 - Bandera, E V A1 - Becker, D M A1 - Becker, L A1 - Berndt, S I A1 - Bernstein, L A1 - Blot, W J A1 - Broeckel, U A1 - Buxbaum, S G A1 - Caporaso, N A1 - Casey, G A1 - Chanock, S J A1 - Deming, S L A1 - Diver, W R A1 - Eaton, C B A1 - Evans, D S A1 - Evans, M K A1 - Fornage, M A1 - Franceschini, N A1 - Harris, T B A1 - Henderson, B E A1 - Hernandez, D G A1 - Hitsman, B A1 - Hu, J J A1 - Hunt, S C A1 - Ingles, S A A1 - John, E M A1 - Kittles, R A1 - Kolb, S A1 - Kolonel, L N A1 - Le Marchand, L A1 - Liu, Y A1 - Lohman, K K A1 - McKnight, B A1 - Millikan, R C A1 - Murphy, A A1 - Neslund-Dudas, C A1 - Nyante, S A1 - Press, M A1 - Psaty, B M A1 - Rao, D C A1 - Redline, S A1 - Rodriguez-Gil, J L A1 - Rybicki, B A A1 - Signorello, L B A1 - Singleton, A B A1 - Smoller, J A1 - Snively, B A1 - Spring, B A1 - Stanford, J L A1 - Strom, S S A1 - Swan, G E A1 - Taylor, K D A1 - Thun, M J A1 - Wilson, A F A1 - Witte, J S A1 - Yamamura, Y A1 - Yanek, L R A1 - Yu, K A1 - Zheng, W A1 - Ziegler, R G A1 - Zonderman, A B A1 - Jorgenson, E A1 - Haiman, C A A1 - Furberg, H KW - Adult KW - African Americans KW - Aged KW - Chromosomes, Human, Pair 10 KW - Chromosomes, Human, Pair 15 KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proteoglycans KW - Receptors, Nicotinic KW - Smoking KW - Statistics as Topic AB -

The 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.

VL - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22832964?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. JF - Nat Genet Y1 - 2012 A1 - Estrada, Karol A1 - Styrkarsdottir, Unnur A1 - Evangelou, Evangelos A1 - Hsu, Yi-Hsiang A1 - Duncan, Emma L A1 - Ntzani, Evangelia E A1 - Oei, Ling A1 - Albagha, Omar M E A1 - Amin, Najaf A1 - Kemp, John P A1 - Koller, Daniel L A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Minster, Ryan L A1 - Moayyeri, Alireza A1 - Vandenput, Liesbeth A1 - Willner, Dana A1 - Xiao, Su-Mei A1 - Yerges-Armstrong, Laura M A1 - Zheng, Hou-Feng A1 - Alonso, Nerea A1 - Eriksson, Joel A1 - Kammerer, Candace M A1 - Kaptoge, Stephen K A1 - Leo, Paul J A1 - Thorleifsson, Gudmar A1 - Wilson, Scott G A1 - Wilson, James F A1 - Aalto, Ville A1 - Alen, Markku A1 - Aragaki, Aaron K A1 - Aspelund, Thor A1 - Center, Jacqueline R A1 - Dailiana, Zoe A1 - Duggan, David J A1 - Garcia, Melissa A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Hallmans, Göran A1 - Hocking, Lynne J A1 - Husted, Lise Bjerre A1 - Jameson, Karen A A1 - Khusainova, Rita A1 - Kim, Ghi Su A1 - Kooperberg, Charles A1 - Koromila, Theodora A1 - Kruk, Marcin A1 - Laaksonen, Marika A1 - LaCroix, Andrea Z A1 - Lee, Seung Hun A1 - Leung, Ping C A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nguyen, Tuan V A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Rose, Lynda M A1 - Scollen, Serena A1 - Siggeirsdottir, Kristin A1 - Smith, Albert V A1 - Svensson, Olle A1 - Trompet, Stella A1 - Trummer, Olivia A1 - van Schoor, Natasja M A1 - Woo, Jean A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Buckley, Brendan M A1 - Cheng, Sulin A1 - Christiansen, Claus A1 - Cooper, Cyrus A1 - Dedoussis, George A1 - Ford, Ian A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Kähönen, Mika A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza A1 - Koh, Jung-Min A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Leslie, William D A1 - Lips, Paul A1 - Ljunggren, Osten A1 - Lorenc, Roman S A1 - Marc, Janja A1 - Mellström, Dan A1 - Obermayer-Pietsch, Barbara A1 - Olmos, José M A1 - Pettersson-Kymmer, Ulrika A1 - Reid, David M A1 - Riancho, José A A1 - Ridker, Paul M A1 - Rousseau, François A1 - Slagboom, P Eline A1 - Tang, Nelson L S A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Viikari, Jorma A1 - Zarrabeitia, María T A1 - Aulchenko, Yurii S A1 - Castano-Betancourt, Martha A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Ingvarsson, Thorvaldur A1 - Johannsdottir, Hrefna A1 - Kwan, Tony A1 - Li, Rui A1 - Luben, Robert A1 - Medina-Gómez, Carolina A1 - Palsson, Stefan Th A1 - Reppe, Sjur A1 - Rotter, Jerome I A1 - Sigurdsson, Gunnar A1 - van Meurs, Joyce B J A1 - Verlaan, Dominique A1 - Williams, Frances M K A1 - Wood, Andrew R A1 - Zhou, Yanhua A1 - Gautvik, Kaare M A1 - Pastinen, Tomi A1 - Raychaudhuri, Soumya A1 - Cauley, Jane A A1 - Chasman, Daniel I A1 - Clark, Graeme R A1 - Cummings, Steven R A1 - Danoy, Patrick A1 - Dennison, Elaine M A1 - Eastell, Richard A1 - Eisman, John A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Jackson, Rebecca D A1 - Jones, Graeme A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Lorentzon, Mattias A1 - McCloskey, Eugene A1 - Mitchell, Braxton D A1 - Nandakumar, Kannabiran A1 - Nicholson, Geoffrey C A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Pols, Huibert A P A1 - Prince, Richard L A1 - Raitakari, Olli A1 - Reid, Ian R A1 - Robbins, John A1 - Sambrook, Philip N A1 - Sham, Pak Chung A1 - Shuldiner, Alan R A1 - Tylavsky, Frances A A1 - van Duijn, Cornelia M A1 - Wareham, Nick J A1 - Cupples, L Adrienne A1 - Econs, Michael J A1 - Evans, David M A1 - Harris, Tamara B A1 - Kung, Annie Wai Chee A1 - Psaty, Bruce M A1 - Reeve, Jonathan A1 - Spector, Timothy D A1 - Streeten, Elizabeth A A1 - Zillikens, M Carola A1 - Thorsteinsdottir, Unnur A1 - Ohlsson, Claes A1 - Karasik, David A1 - Richards, J Brent A1 - Brown, Matthew A A1 - Stefansson, Kari A1 - Uitterlinden, André G A1 - Ralston, Stuart H A1 - Ioannidis, John P A A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando KW - Bone Density KW - Computational Biology KW - European Continental Ancestry Group KW - Extracellular Matrix Proteins KW - Female KW - Femur Neck KW - Fractures, Bone KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Glycoproteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-5 KW - Lumbar Vertebrae KW - Male KW - Mitochondrial Membrane Transport Proteins KW - Osteoporosis KW - Phosphoproteins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Spectrin AB -

Bone 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.

VL - 44 IS - 5 ER - TY - JOUR T1 - Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. JF - Hum Mol Genet Y1 - 2012 A1 - Mangino, Massimo A1 - Hwang, Shih-Jen A1 - Spector, Timothy D A1 - Hunt, Steven C A1 - Kimura, Masayuki A1 - Fitzpatrick, Annette L A1 - Christiansen, Lene A1 - Petersen, Inge A1 - Elbers, Clara C A1 - Harris, Tamara A1 - Chen, Wei A1 - Srinivasan, Sathanur R A1 - Kark, Jeremy D A1 - Benetos, Athanase A1 - El Shamieh, Said A1 - Visvikis-Siest, Sophie A1 - Christensen, Kaare A1 - Berenson, Gerald S A1 - Valdes, Ana M A1 - Viñuela, Ana A1 - Garcia, Melissa A1 - Arnett, Donna K A1 - Broeckel, Ulrich A1 - Province, Michael A A1 - Pankow, James S A1 - Kammerer, Candace A1 - Liu, Yongmei A1 - Nalls, Michael A1 - Tishkoff, Sarah A1 - Thomas, Fridtjof A1 - Ziv, Elad A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Smith, Erin A1 - Schork, Nicholas J A1 - Levy, Daniel A1 - Aviv, Abraham KW - Genome-Wide Association Study KW - Humans KW - Kruppel-Like Transcription Factors KW - Telomere KW - Telomere Homeostasis KW - Telomere-Binding Proteins AB -

Leukocyte 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.

VL - 21 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23001564?dopt=Abstract ER - TY - JOUR T1 - Hemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study. JF - Int J Mol Epidemiol Genet Y1 - 2012 A1 - Suchy-Dicey, Astrid M A1 - Enquobahrie, Daniel A A1 - Heckbert, Susan R A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - McKnight, Barbara AB -

OBJECTIVE: 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.

VL - 3 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22724054?dopt=Abstract ER - TY - JOUR T1 - Impact of ancestry and common genetic variants on QT interval in African Americans. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Smith, J Gustav A1 - Avery, Christy L A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Meng, Yan A A1 - Smith, Erin N A1 - Palmer, Cameron A1 - Tanaka, Toshiko A1 - Mehra, Reena A1 - Butler, Anne M A1 - Young, Taylor A1 - Buxbaum, Sarah G A1 - Kerr, Kathleen F A1 - Berenson, Gerald S A1 - Schnabel, Renate B A1 - Li, Guo A1 - Ellinor, Patrick T A1 - Magnani, Jared W A1 - Chen, Wei A1 - Bis, Joshua C A1 - Curb, J David A1 - Hsueh, Wen-Chi A1 - Rotter, Jerome I A1 - Liu, Yongmei A1 - Newman, Anne B A1 - Limacher, Marian C A1 - North, Kari E A1 - Reiner, Alexander P A1 - Quibrera, P Miguel A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Solomon, Allen J A1 - Srinivasan, Sathanur R A1 - Alonso, Alvaro A1 - Wallace, Robert A1 - Redline, Susan A1 - Zhang, Zhu-Ming A1 - Post, Wendy S A1 - Zonderman, Alan B A1 - Taylor, Herman A A1 - Murray, Sarah S A1 - Ferrucci, Luigi A1 - Arking, Dan E A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - Newton-Cheh, Christopher KW - Adult KW - African Americans KW - Aged KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genealogy and Heraldry KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract ER - TY - JOUR T1 - The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study. JF - Eur Heart J Y1 - 2012 A1 - Rosenberg, Michael A A1 - Patton, Kristen K A1 - Sotoodehnia, Nona A1 - Karas, Maria G A1 - Kizer, Jorge R A1 - Zimetbaum, Peter J A1 - Chang, James D A1 - Siscovick, David A1 - Gottdiener, John S A1 - Kronmal, Richard A A1 - Heckbert, Susan R A1 - Mukamal, Kenneth J KW - Aged KW - Atrial Fibrillation KW - Body Height KW - Epidemiologic Methods KW - Female KW - Humans KW - Male KW - Sex Factors KW - United States AB -

AIMS: 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.

VL - 33 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22977225?dopt=Abstract ER - TY - JOUR T1 - Insulin resistance, cystatin C, and mortality among older adults. JF - Diabetes Care Y1 - 2012 A1 - de Boer, Ian H A1 - Katz, Ronit A1 - Chonchol, Michel B A1 - Fried, Linda F A1 - Ix, Joachim H A1 - Kestenbaum, Bryan A1 - Mukamal, Kenneth J A1 - Peralta, Carmen A A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Blood Pressure KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Cystatin C KW - Fasting KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Insulin Resistance KW - Life Style KW - Male KW - Mortality KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Renal Insufficiency KW - Risk Factors KW - Triglycerides KW - Waist Circumference AB -

OBJECTIVE: 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.

VL - 35 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22432118?dopt=Abstract ER - TY - JOUR T1 - Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars. JF - J Am Geriatr Soc Y1 - 2012 A1 - Shastri, Shani A1 - Katz, Ronit A1 - Rifkin, Dena E A1 - Fried, Linda F A1 - Odden, Michelle C A1 - Peralta, Carmen A A1 - Chonchol, Michel A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Newman, Anne B A1 - Sarnak, Mark J KW - Aged, 80 and over KW - Analysis of Variance KW - Cardiovascular Diseases KW - Chi-Square Distribution KW - Creatinine KW - Cystatin C KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney Diseases KW - Male KW - Prevalence KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Factors KW - United States AB -

OBJECTIVES: 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) .

VL - 60 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22724391?dopt=Abstract ER - TY - JOUR T1 - Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. JF - Nat Genet Y1 - 2012 A1 - Scott, Robert A A1 - Lagou, Vasiliki A1 - Welch, Ryan P A1 - Wheeler, Eleanor A1 - Montasser, May E A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Rehnberg, Emil A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Rasmussen-Torvik, Laura J A1 - Yengo, Loic A1 - Lecoeur, Cécile A1 - Shungin, Dmitry A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Johnson, Paul C D A1 - Jukema, J Wouter A1 - Johnson, Toby A1 - Mahajan, Anubha A1 - Verweij, Niek A1 - Thorleifsson, Gudmar A1 - Hottenga, Jouke-Jan A1 - Shah, Sonia A1 - Smith, Albert V A1 - Sennblad, Bengt A1 - Gieger, Christian A1 - Salo, Perttu A1 - Perola, Markus A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Pourcain, Beate St A1 - Wu, Ying A1 - Andrews, Jeanette S A1 - Hui, Jennie A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Horikoshi, Momoko A1 - Navarro, Pau A1 - Isaacs, Aaron A1 - O'Connell, Jeffrey R A1 - Stirrups, Kathleen A1 - Vitart, Veronique A1 - Hayward, Caroline A1 - Esko, Tõnu A1 - Mihailov, Evelin A1 - Fraser, Ross M A1 - Fall, Tove A1 - Voight, Benjamin F A1 - Raychaudhuri, Soumya A1 - Chen, Han A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Rayner, Nigel W A1 - Robertson, Neil A1 - Rybin, Denis A1 - Liu, Ching-Ti A1 - Beckmann, Jacques S A1 - Willems, Sara M A1 - Chines, Peter S A1 - Jackson, Anne U A1 - Kang, Hyun Min A1 - Stringham, Heather M A1 - Song, Kijoung A1 - Tanaka, Toshiko A1 - Peden, John F A1 - Goel, Anuj A1 - Hicks, Andrew A A1 - An, Ping A1 - Müller-Nurasyid, Martina A1 - Franco-Cereceda, Anders A1 - Folkersen, Lasse A1 - Marullo, Letizia A1 - Jansen, Hanneke A1 - Oldehinkel, Albertine J A1 - Bruinenberg, Marcel A1 - Pankow, James S A1 - North, Kari E A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Edkins, Sarah A1 - Varga, Tibor V A1 - Hallmans, Göran A1 - Oksa, Heikki A1 - Antonella, Mulas A1 - Nagaraja, Ramaiah A1 - Trompet, Stella A1 - Ford, Ian A1 - Bakker, Stephan J L A1 - Kong, Augustine A1 - Kumari, Meena A1 - Gigante, Bruna A1 - Herder, Christian A1 - Munroe, Patricia B A1 - Caulfield, Mark A1 - Antti, Jula A1 - Mangino, Massimo A1 - Small, Kerrin A1 - Miljkovic, Iva A1 - Liu, Yongmei A1 - Atalay, Mustafa A1 - Kiess, Wieland A1 - James, Alan L A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Palmer, Colin N A A1 - Doney, Alex S F A1 - Willemsen, Gonneke A1 - Smit, Johannes H A1 - Campbell, Susan A1 - Polasek, Ozren A1 - Bonnycastle, Lori L A1 - Hercberg, Serge A1 - Dimitriou, Maria A1 - Bolton, Jennifer L A1 - Fowkes, Gerard R A1 - Kovacs, Peter A1 - Lindström, Jaana A1 - Zemunik, Tatijana A1 - Bandinelli, Stefania A1 - Wild, Sarah H A1 - Basart, Hanneke V A1 - Rathmann, Wolfgang A1 - Grallert, Harald A1 - Maerz, Winfried A1 - Kleber, Marcus E A1 - Boehm, Bernhard O A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Province, Michael A A1 - Borecki, Ingrid B A1 - Hastie, Nicholas D A1 - Rudan, Igor A1 - Campbell, Harry A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Stumvoll, Michael A1 - Ferrucci, Luigi A1 - Waterworth, Dawn M A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Tuomilehto, Jaakko A1 - Watanabe, Richard M A1 - de Geus, Eco J C A1 - Penninx, Brenda W A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Wright, Alan F A1 - Hovingh, G Kees A1 - Metspalu, Andres A1 - Uusitupa, Matti A1 - Magnusson, Patrik K E A1 - Kyvik, Kirsten O A1 - Kaprio, Jaakko A1 - Price, Jackie F A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Meneton, Pierre A1 - Lind, Lars A1 - Boehnke, Michael A1 - Shuldiner, Alan R A1 - van Duijn, Cornelia M A1 - Morris, Andrew D A1 - Toenjes, Anke A1 - Peyser, Patricia A A1 - Beilby, John P A1 - Körner, Antje A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Adair, Linda S A1 - Smith, George Davey A1 - Spector, Tim D A1 - Illig, Thomas A1 - de Faire, Ulf A1 - Hamsten, Anders A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Hingorani, Aroon A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Boomsma, Dorret I A1 - Stefansson, Kari A1 - van der Harst, Pim A1 - Dupuis, Josée A1 - Pedersen, Nancy L A1 - Sattar, Naveed A1 - Harris, Tamara B A1 - Cucca, Francesco A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Mohlke, Karen L A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Pouta, Anneli A1 - Jarvelin, Marjo-Riitta A1 - Wareham, Nicholas J A1 - Bouatia-Naji, Nabila A1 - McCarthy, Mark I A1 - Franks, Paul W A1 - Meigs, James B A1 - Teslovich, Tanya M A1 - Florez, Jose C A1 - Langenberg, Claudia A1 - Ingelsson, Erik A1 - Prokopenko, Inga A1 - Barroso, Inês KW - Adult KW - Animals KW - Blood Glucose KW - Fasting KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Osmolar Concentration KW - Quantitative Trait Loci AB -

Through 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.

VL - 44 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract ER - TY - JOUR T1 - Large-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts. JF - BMJ Open Y1 - 2012 A1 - Puhan, Milo A A1 - Hansel, Nadia N A1 - Sobradillo, Patricia A1 - Enright, Paul A1 - Lange, Peter A1 - Hickson, Demarc A1 - Menezes, Ana M A1 - ter Riet, Gerben A1 - Held, Ulrike A1 - Domingo-Salvany, Antonia A1 - Mosenifar, Zab A1 - Antó, Josep M A1 - Moons, Karel G M A1 - Kessels, Alphons A1 - Garcia-Aymerich, Judith AB -

BACKGROUND: 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.

VL - 2 IS - 6 ER - TY - JOUR T1 - Lipid-related markers and cardiovascular disease prediction. JF - JAMA Y1 - 2012 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Pennells, Lisa A1 - Kaptoge, Stephen A1 - Caslake, Muriel A1 - Thompson, Alexander A1 - Butterworth, Adam S A1 - Sarwar, Nadeem A1 - Wormser, David A1 - Saleheen, Danish A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Sundström, Johan A1 - Ridker, Paul M A1 - Nagel, Dorothea A1 - Gillum, Richard F A1 - Ford, Ian A1 - Ducimetiere, Pierre A1 - Kiechl, Stefan A1 - Koenig, Wolfgang A1 - Dullaart, Robin P F A1 - Assmann, Gerd A1 - D'Agostino, Ralph B A1 - Dagenais, Gilles R A1 - Cooper, Jackie A A1 - Kromhout, Daan A1 - Onat, Altan A1 - Tipping, Robert W A1 - Gómez-de-la-Cámara, Agustín A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Gallacher, John A1 - Fowkes, F Gerry R A1 - Casiglia, Edoardo A1 - Hofman, Albert A1 - Salomaa, Veikko A1 - Barrett-Connor, Elizabeth A1 - Clarke, Robert A1 - Brunner, Eric A1 - Jukema, J Wouter A1 - Simons, Leon A A1 - Sandhu, Manjinder A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Howard, William J A1 - Nordestgaard, Børge G A1 - Wood, Angela M A1 - Thompson, Simon G A1 - Boekholdt, S Matthijs A1 - Sattar, Naveed A1 - Packard, Chris A1 - Gudnason, Vilmundur A1 - Danesh, John KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cohort Studies KW - Female KW - Humans KW - Lipoproteins KW - Male KW - Middle Aged KW - Risk Assessment AB -

CONTEXT: 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.

VL - 307 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22797450?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To 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.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies six new susceptibility loci for atrial fibrillation. JF - Nat Genet Y1 - 2012 A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Albert, Christine M A1 - Glazer, Nicole L A1 - Ritchie, Marylyn D A1 - Smith, Albert V A1 - Arking, Dan E A1 - Müller-Nurasyid, Martina A1 - Krijthe, Bouwe P A1 - Lubitz, Steven A A1 - Bis, Joshua C A1 - Chung, Mina K A1 - Dörr, Marcus A1 - Ozaki, Kouichi A1 - Roberts, Jason D A1 - Smith, J Gustav A1 - Pfeufer, Arne A1 - Sinner, Moritz F A1 - Lohman, Kurt A1 - Ding, Jingzhong A1 - Smith, Nicholas L A1 - Smith, Jonathan D A1 - Rienstra, Michiel A1 - Rice, Kenneth M A1 - Van Wagoner, David R A1 - Magnani, Jared W A1 - Wakili, Reza A1 - Clauss, Sebastian A1 - Rotter, Jerome I A1 - Steinbeck, Gerhard A1 - Launer, Lenore J A1 - Davies, Robert W A1 - Borkovich, Matthew A1 - Harris, Tamara B A1 - Lin, Honghuang A1 - Völker, Uwe A1 - Völzke, Henry A1 - Milan, David J A1 - Hofman, Albert A1 - Boerwinkle, Eric A1 - Chen, Lin Y A1 - Soliman, Elsayed Z A1 - Voight, Benjamin F A1 - Li, Guo A1 - Chakravarti, Aravinda A1 - Kubo, Michiaki A1 - Tedrow, Usha B A1 - Rose, Lynda M A1 - Ridker, Paul M A1 - Conen, David A1 - Tsunoda, Tatsuhiko A1 - Furukawa, Tetsushi A1 - Sotoodehnia, Nona A1 - Xu, Siyan A1 - Kamatani, Naoyuki A1 - Levy, Daniel A1 - Nakamura, Yusuke A1 - Parvez, Babar A1 - Mahida, Saagar A1 - Furie, Karen L A1 - Rosand, Jonathan A1 - Muhammad, Raafia A1 - Psaty, Bruce M A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Wichmann, H-Erich A1 - Witteman, Jacqueline C M A1 - Kao, W H Linda A1 - Kathiresan, Sekar A1 - Roden, Dan M A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - McKnight, Barbara A1 - Sjögren, Marketa A1 - Newman, Anne B A1 - Liu, Yongmei A1 - Gollob, Michael H A1 - Melander, Olle A1 - Tanaka, Toshihiro A1 - Stricker, Bruno H Ch A1 - Felix, Stephan B A1 - Alonso, Alvaro A1 - Darbar, Dawood A1 - Barnard, John A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Gudnason, Vilmundur A1 - Kääb, Stefan KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Atrial Fibrillation KW - Child KW - Child, Preschool KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Infant KW - Infant, Newborn KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Young Adult AB -

Atrial 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.

VL - 44 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22544366?dopt=Abstract ER - TY - JOUR T1 - Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project. JF - PLoS One Y1 - 2012 A1 - Musunuru, Kiran A1 - Romaine, Simon P R A1 - Lettre, Guillaume A1 - Wilson, James G A1 - Volcik, Kelly A A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Schreiner, Pamela J A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Papanicolaou, George J A1 - Ordovas, Jose M A1 - Liu, Kiang A1 - Krauss, Ronald M A1 - Glazer, Nicole L A1 - Gabriel, Stacey B A1 - Fornage, Myriam A1 - Cupples, L Adrienne A1 - Buxbaum, Sarah G A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Kathiresan, Sekar A1 - Rader, Daniel J KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Loci KW - Humans KW - Polymorphism, Single Nucleotide KW - Triglycerides AB -

BACKGROUND: 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.

VL - 7 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22629316?dopt=Abstract ER - TY - JOUR T1 - Nocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort. JF - PLoS One Y1 - 2012 A1 - Parthasarathy, Sairam A1 - Fitzgerald, MaryPat A1 - Goodwin, James L A1 - Unruh, Mark A1 - Guerra, Stefano A1 - Quan, Stuart F KW - Aged KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Nocturia KW - Polysomnography KW - Sleep Apnea Syndromes AB -

BACKGROUND: 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.

VL - 7 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22328924?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Butler, Anne M A1 - Yin, Xiaoyan A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Buxbaum, Sarah G A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Berenson, Gerald S A1 - Bis, Josh C A1 - Chen, Wei A1 - Deo, Rajat A1 - Ellinor, Patrick T A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hsueh, Wen-Chi A1 - Keating, Brendan J A1 - Kerr, Kathleen F A1 - Li, Yun A1 - Limacher, Marian C A1 - Liu, Yongmei A1 - Lubitz, Steven A A1 - Marciante, Kristin D A1 - Mehra, Reena A1 - Meng, Yan A A1 - Newman, Anne B A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Palmer, Cameron D A1 - Psaty, Bruce M A1 - Quibrera, P Miguel A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Evans, Michele K A1 - Sotoodehnia, Nona A1 - Magnani, Jared W A1 - Avery, Christy L KW - Adult KW - African Americans KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Circulating 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.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Predicting late-life disability and death by the rate of decline in physical performance measures. JF - Age Ageing Y1 - 2012 A1 - Hirsch, Calvin Hayes A1 - Bůzková, Petra A1 - Robbins, John A A1 - Patel, Kushang V A1 - Newman, Anne B KW - Activities of Daily Living KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Disability Evaluation KW - Disabled Persons KW - Female KW - Geriatric Assessment KW - Hand Strength KW - Health Surveys KW - Humans KW - Linear Models KW - Male KW - Mobility Limitation KW - Mortality KW - Motor Skills KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - Survival Analysis KW - Time Factors KW - United States KW - Upper Extremity KW - Walking AB -

BACKGROUND: 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.

VL - 41 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22156556?dopt=Abstract ER - TY - JOUR T1 - Probabilistic sleep architecture models in patients with and without sleep apnea. JF - J Sleep Res Y1 - 2012 A1 - Bianchi, Matt T A1 - Eiseman, Nathaniel A A1 - Cash, Sydney S A1 - Mietus, Joseph A1 - Peng, Chung-Kang A1 - Thomas, Robert J KW - Cohort Studies KW - Computer Simulation KW - Humans KW - Models, Theoretical KW - Polysomnography KW - Probability KW - Sleep Apnea Syndromes KW - Sleep Stages KW - Sleep, REM KW - Time Factors AB -

Sleep 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.

VL - 21 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21955148?dopt=Abstract ER - TY - JOUR T1 - Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. JF - Ann Neurol Y1 - 2012 A1 - Folsom, Aaron R A1 - Yatsuya, Hiroshi A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Longstreth, W T KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Intracranial Hemorrhages KW - Leukoaraiosis KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Risk Factors AB -

OBJECTIVE: 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.

VL - 71 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22522444?dopt=Abstract ER - TY - JOUR T1 - A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel. JF - Clin Pharmacol Ther Y1 - 2012 A1 - Floyd, J S A1 - Kaspera, R A1 - Marciante, K D A1 - Weiss, N S A1 - Heckbert, S R A1 - Lumley, T A1 - Wiggins, K L A1 - Tamraz, B A1 - Kwok, P-Y A1 - Totah, R A A1 - Psaty, B M KW - Adverse Drug Reaction Reporting Systems KW - Aged KW - Aged, 80 and over KW - Aryl Hydrocarbon Hydroxylases KW - Case-Control Studies KW - Cytochrome P-450 CYP2C8 KW - Cytochrome P-450 CYP3A KW - Cytochrome P-450 CYP3A Inhibitors KW - Drug Interactions KW - Female KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Male KW - Platelet Aggregation Inhibitors KW - Pyridines KW - Rhabdomyolysis KW - Ticlopidine AB -

An 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.

VL - 91 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22419147?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and caffeine consumption: results of a community-based study. JF - Chest Y1 - 2012 A1 - Aurora, R Nisha A1 - Crainiceanu, Ciprian A1 - Caffo, Brian A1 - Punjabi, Naresh M KW - Age Factors KW - Aged KW - Caffeine KW - Carbonated Beverages KW - Coffee KW - Data Collection KW - Drinking Behavior KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Prevalence KW - Retrospective Studies KW - Sex Factors KW - Sleep Apnea Syndromes KW - Tea AB -

BACKGROUND: 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.

VL - 142 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22459776?dopt=Abstract ER - TY - JOUR T1 - Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study. JF - Mech Ageing Dev Y1 - 2012 A1 - Burnett-Hartman, Andrea N A1 - Fitzpatrick, Annette L A1 - Kronmal, Richard A A1 - Psaty, Bruce M A1 - Jenny, Nancy S A1 - Bis, Josh C A1 - Tracy, Russ P A1 - Kimura, Masayuki A1 - Aviv, Abraham KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Leukocytes KW - Male KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - Risk KW - RNA KW - Sex Factors KW - Telomerase KW - Telomere AB -

Leukocyte 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.

VL - 133 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22449406?dopt=Abstract ER - TY - JOUR T1 - Transforming growth factor beta-1 and incidence of heart failure in older adults: the Cardiovascular Health Study. JF - Cytokine Y1 - 2012 A1 - Glazer, Nicole L A1 - Macy, Elizabeth M A1 - Lumley, Thomas A1 - Smith, Nicholas L A1 - Reiner, Alex P A1 - Psaty, Bruce M A1 - King, George L A1 - Tracy, Russell P A1 - Siscovick, David S KW - Aged KW - Case-Control Studies KW - Health KW - Heart Failure KW - Humans KW - Incidence KW - Transforming Growth Factor beta1 KW - United States AB -

CONTEXT: 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.

VL - 60 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22878343?dopt=Abstract ER - TY - JOUR T1 - Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. JF - Genetics Y1 - 2012 A1 - Chiang, Charleston W K A1 - Liu, Ching-Ti A1 - Lettre, Guillaume A1 - Lange, Leslie A A1 - Jorgensen, Neal W A1 - Keating, Brendan J A1 - Vedantam, Sailaja A1 - Nock, Nora L A1 - Franceschini, Nora A1 - Reiner, Alex P A1 - Demerath, Ellen W A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Wilson, James G A1 - North, Kari E A1 - Papanicolaou, George J A1 - Cupples, L Adrienne A1 - Murabito, Joanne M A1 - Hirschhorn, Joel N KW - Alleles KW - Animals KW - Body Height KW - Body Mass Index KW - Child KW - Conserved Sequence KW - Dogs KW - Evolution, Molecular KW - Female KW - Genetic Fitness KW - Genetic Variation KW - Genome, Human KW - Genotype KW - Humans KW - Inheritance Patterns KW - Male KW - Mice KW - Pedigree KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Rats KW - Reproduction KW - Young Adult AB -

Ultraconserved 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.

VL - 192 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22714408?dopt=Abstract ER - TY - JOUR T1 - Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts. JF - Biomarkers Y1 - 2013 A1 - Oelsner, E C A1 - Pottinger, T D A1 - Burkart, K M A1 - Allison, M A1 - Buxbaum, S G A1 - Hansel, N N A1 - Kumar, R A1 - Larkin, E K A1 - Lange, L A A1 - Loehr, L R A1 - London, S J A1 - O'Connor, G T A1 - Papanicolaou, G A1 - Petrini, M F A1 - Rabinowitz, D A1 - Raghavan, S A1 - Redline, S A1 - Thyagarajan, B A1 - Tracy, R P A1 - Wilk, J B A1 - White, W B A1 - Rich, S S A1 - Barr, R G KW - African Continental Ancestry Group KW - Biomarkers KW - Cohort Studies KW - E-Selectin KW - Endothelin-1 KW - Endothelium, Vascular KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Humans KW - Intercellular Adhesion Molecule-1 KW - Lung KW - Male KW - Middle Aged KW - P-Selectin KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests KW - Spirometry AB -

CONTEXT: 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.

VL - 18 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23557128?dopt=Abstract ER - TY - JOUR T1 - Association 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. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Yu, Bing A1 - Barbalic, Maja A1 - Brautbar, Ariel A1 - Nambi, Vijay A1 - Hoogeveen, Ron C A1 - Tang, Weihong A1 - Mosley, Thomas H A1 - Rotter, Jerome I A1 - deFilippi, Christopher R A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Rice, Ken A1 - Heckbert, Susan R A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric KW - African Continental Ancestry Group KW - Atherosclerosis KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nuclear Receptor Coactivator 2 KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Residence Characteristics KW - Risk Factors KW - Troponin T AB -

BACKGROUND: 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.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23247143?dopt=Abstract ER - TY - JOUR T1 - Association of heat shock proteins with all-cause mortality. JF - Age (Dordr) Y1 - 2013 A1 - Broer, L A1 - Demerath, E W A1 - Garcia, M E A1 - Homuth, G A1 - Kaplan, R C A1 - Lunetta, K L A1 - Tanaka, T A1 - Tranah, G J A1 - Walter, S A1 - Arnold, A M A1 - Atzmon, G A1 - Harris, T B A1 - Hoffmann, W A1 - Karasik, D A1 - Kiel, D P A1 - Kocher, T A1 - Launer, L J A1 - Lohman, K K A1 - Rotter, J I A1 - Tiemeier, H A1 - Uitterlinden, A G A1 - Wallaschofski, H A1 - Bandinelli, S A1 - Dörr, M A1 - Ferrucci, L A1 - Franceschini, N A1 - Gudnason, V A1 - Hofman, A A1 - Liu, Y A1 - Murabito, J M A1 - Newman, A B A1 - Oostra, B A A1 - Psaty, B M A1 - Smith, A V A1 - van Duijn, C M KW - Aged, 80 and over KW - Aging KW - Cause of Death KW - Forecasting KW - Genotype KW - Heat-Shock Proteins KW - Humans KW - Longevity KW - Promoter Regions, Genetic KW - Retrospective Studies KW - Transcription, Genetic KW - United States AB -

Experimental 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.

VL - 35 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22555621?dopt=Abstract ER - TY - JOUR T1 - Associations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2013 A1 - Fretts, Amanda M A1 - Mozaffarian, Dariush A1 - Siscovick, David S A1 - Heckbert, Susan R A1 - McKnight, Barbara A1 - King, Irena B A1 - Rimm, Eric B A1 - Psaty, Bruce M A1 - Sacks, Frank M A1 - Song, Xiaoling A1 - Spiegelman, Donna A1 - Lemaitre, Rozenn N KW - Age Factors KW - Aged KW - Aged, 80 and over KW - alpha-Linolenic Acid KW - Atrial Fibrillation KW - Biomarkers KW - Diet KW - Female KW - Humans KW - Incidence KW - Linear Models KW - Longitudinal Studies KW - Male KW - Nutritional Status KW - Phospholipids KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

BACKGROUND: 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.

VL - 2 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23525429?dopt=Abstract ER - TY - JOUR T1 - Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. JF - Ann Intern Med Y1 - 2013 A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Mandyam, Mala C A1 - Heckbert, Susan R A1 - Siscovick, David S A1 - Stein, Phyllis K A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Gottdiener, John S A1 - Marcus, Gregory M KW - Aged KW - Atrial Fibrillation KW - Atrial Function KW - Cause of Death KW - Electrocardiography KW - Female KW - Humans KW - Male KW - Models, Statistical KW - Myocardial Contraction KW - Prospective Studies KW - Risk Assessment AB -

BACKGROUND: 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.

VL - 159 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24297188?dopt=Abstract ER - TY - JOUR T1 - Atrial fibrillation and cognitive decline: a longitudinal cohort study. JF - Neurology Y1 - 2013 A1 - Thacker, Evan L A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Sitlani, Colleen M A1 - Dublin, Sascha A1 - Arnold, Alice M A1 - Fitzpatrick, Annette L A1 - Gottesman, Rebecca F A1 - Heckbert, Susan R KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cognition Disorders KW - Comorbidity KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Luria-Nebraska Neuropsychological Battery KW - Male KW - Predictive Value of Tests AB -

OBJECTIVE: 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.

VL - 81 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23739229?dopt=Abstract ER - TY - JOUR T1 - Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. JF - JAMA Intern Med Y1 - 2013 A1 - Chen, Lin Y A1 - Sotoodehnia, Nona A1 - Bůzková, Petra A1 - Lopez, Faye L A1 - Yee, Laura M A1 - Heckbert, Susan R A1 - Prineas, Ronald A1 - Soliman, Elsayed Z A1 - Adabag, Selcuk A1 - Konety, Suma A1 - Folsom, Aaron R A1 - Siscovick, David A1 - Alonso, Alvaro KW - Aged KW - Atrial Fibrillation KW - Cardiovascular Diseases KW - Death, Sudden, Cardiac KW - Demography KW - Ethnic Groups KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - United States AB -

BACKGROUND: 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.

VL - 173 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23404043?dopt=Abstract ER - TY - JOUR T1 - Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. JF - PLoS One Y1 - 2013 A1 - Grove, Megan L A1 - Yu, Bing A1 - Cochran, Barbara J A1 - Haritunians, Talin A1 - Bis, Joshua C A1 - Taylor, Kent D A1 - Hansen, Mark A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Kathiresan, Sekar A1 - Kraaij, Robert A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Mosley, Thomas A1 - Peloso, Gina M A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Siscovick, David S A1 - Smith, Albert V A1 - Uitterlinden, Andre A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Boerwinkle, Eric KW - Aging KW - Alleles KW - Cluster Analysis KW - Cohort Studies KW - Continental Population Groups KW - Exome KW - Female KW - Gene Frequency KW - Genomics KW - Genotype KW - Heart KW - Humans KW - Male KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Sample Size KW - Self Report KW - Sequence Analysis, DNA AB -

Genotyping 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.

VL - 8 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23874508?dopt=Abstract ER - TY - JOUR T1 - Bidirectional relationship between cognitive function and pneumonia. JF - Am J Respir Crit Care Med Y1 - 2013 A1 - Shah, Faraaz Ali A1 - Pike, Francis A1 - Alvarez, Karina A1 - Angus, Derek A1 - Newman, Anne B A1 - Lopez, Oscar A1 - Tate, Judith A1 - Kapur, Vishesh A1 - Wilsdon, Anthony A1 - Krishnan, Jerry A A1 - Hansel, Nadia A1 - Au, David A1 - Avdalovic, Mark A1 - Fan, Vincent S A1 - Barr, R Graham A1 - Yende, Sachin KW - Aged KW - Cognition Disorders KW - Dementia KW - Female KW - Hospitalization KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Pneumonia KW - Proportional Hazards Models KW - Risk Factors AB -

RATIONALE: 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.

VL - 188 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23848267?dopt=Abstract ER - TY - JOUR T1 - Blood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2013 A1 - Rifkin, Dena E A1 - Katz, Ronit A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Newman, Anne B A1 - Siscovick, David S A1 - Peralta, Carmen A KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Cystatin C KW - Diastole KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Pulse KW - Renal Insufficiency, Chronic KW - Systole AB -

BACKGROUND: 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.

VL - 26 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23709568?dopt=Abstract ER - TY - JOUR T1 - Blood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study. JF - Am J Hypertens Y1 - 2013 A1 - Suchy-Dicey, Astrid M A1 - Wallace, Erin R A1 - Mitchell, S V Elkind A1 - Aguilar, Maria A1 - Gottesman, Rebecca F A1 - Rice, Kenneth A1 - Kronmal, Richard A1 - Psaty, Bruce M A1 - Longstreth, W T KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Mortality KW - Myocardial Infarction KW - Risk KW - Stroke KW - United States AB -

BACKGROUND: 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.

VL - 26 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23744496?dopt=Abstract ER - TY - JOUR T1 - The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science. JF - Epidemiology Y1 - 2013 A1 - Psaty, Bruce M A1 - Sitlani, Colleen KW - Aging KW - Cohort Studies KW - Cooperative Behavior KW - Genome-Wide Association Study KW - Heart Failure KW - Humans KW - Incidence KW - Multicenter Studies as Topic KW - Myocardial Infarction KW - Research Support as Topic KW - Stroke KW - United States VL - 24 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23549178?dopt=Abstract ER - TY - JOUR T1 - Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative. JF - Diabetologia Y1 - 2013 A1 - den Ruijter, H M A1 - Peters, S A E A1 - Groenewegen, K A A1 - Anderson, T J A1 - Britton, A R A1 - Dekker, J M A1 - Engstrom, G A1 - Eijkemans, M J A1 - Evans, G W A1 - de Graaf, J A1 - Grobbee, D E A1 - Hedblad, B A1 - Hofman, A A1 - Holewijn, S A1 - Ikeda, A A1 - Kavousi, M A1 - Kitagawa, K A1 - Kitamura, A A1 - Koffijberg, H A1 - Ikram, M A A1 - Lonn, E M A1 - Lorenz, M W A1 - Mathiesen, E B A1 - Nijpels, G A1 - Okazaki, S A1 - O'Leary, D H A1 - Polak, J F A1 - Price, J F A1 - Robertson, C A1 - Rembold, C M A1 - Rosvall, M A1 - Rundek, T A1 - Salonen, J T A1 - Sitzer, M A1 - Stehouwer, C D A A1 - Witteman, J C A1 - Moons, K G A1 - Bots, M L KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Diabetes Mellitus KW - Humans KW - Myocardial Infarction KW - Risk Factors KW - Stroke AB -

AIMS/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.

VL - 56 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23568273?dopt=Abstract ER - TY - JOUR T1 - Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults. JF - Lipids Y1 - 2013 A1 - Mukamal, Kenneth J A1 - Wilk, Jemma B A1 - Biggs, Mary L A1 - Jensen, Majken K A1 - Ix, Joachim H A1 - Kizer, Jorge R A1 - Tracy, Russell P A1 - Zieman, Susan J A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Djoussé, Luc KW - African Americans KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Fatty Acid-Binding Proteins KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Haplotypes KW - Humans KW - Insulin KW - Linkage Disequilibrium KW - Male KW - Polymorphism, Single Nucleotide AB -

We 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.

VL - 48 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24043587?dopt=Abstract ER - TY - JOUR T1 - Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. JF - Am J Clin Nutr Y1 - 2013 A1 - van Meurs, Joyce B J A1 - Paré, Guillaume A1 - Schwartz, Stephen M A1 - Hazra, Aditi A1 - Tanaka, Toshiko A1 - Vermeulen, Sita H A1 - Cotlarciuc, Ioana A1 - Yuan, Xin A1 - Mälarstig, Anders A1 - Bandinelli, Stefania A1 - Bis, Joshua C A1 - Blom, Henk A1 - Brown, Morris J A1 - Chen, Constance A1 - Chen, Yii-Der A1 - Clarke, Robert J A1 - Dehghan, Abbas A1 - Erdmann, Jeanette A1 - Ferrucci, Luigi A1 - Hamsten, Anders A1 - Hofman, Albert A1 - Hunter, David J A1 - Goel, Anuj A1 - Johnson, Andrew D A1 - Kathiresan, Sekar A1 - Kampman, Ellen A1 - Kiel, Douglas P A1 - Kiemeney, Lambertus A L M A1 - Chambers, John C A1 - Kraft, Peter A1 - Lindemans, Jan A1 - McKnight, Barbara A1 - Nelson, Christopher P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Seedorf, Udo A1 - Siscovick, David S A1 - Schunkert, Heribert A1 - Selhub, Jacob A1 - Ueland, Per M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waterworth, Dawn M A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - den Heijer, Martin A1 - Jacques, Paul A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Rader, Dan J A1 - Reilly, Muredach P A1 - Mooser, Vincent A1 - Chasman, Daniel I A1 - Samani, Nilesh J A1 - Ahmadi, Kourosh R KW - Coronary Artery Disease KW - Genes KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Homocysteine KW - Humans KW - Polymorphism, Genetic KW - Risk Factors AB -

BACKGROUND: 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.

VL - 98 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23824729?dopt=Abstract ER - TY - JOUR T1 - Common 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. JF - Heart Rhythm Y1 - 2013 A1 - Deo, R A1 - Nalls, M A A1 - Avery, C L A1 - Smith, J G A1 - Evans, D S A1 - Keller, M F A1 - Butler, A M A1 - Buxbaum, S G A1 - Li, G A1 - Miguel Quibrera, P A1 - Smith, E N A1 - Tanaka, T A1 - Akylbekova, E L A1 - Alonso, A A1 - Arking, D E A1 - Benjamin, E J A1 - Berenson, G S A1 - Bis, J C A1 - Chen, L Y A1 - Chen, W A1 - Cummings, S R A1 - Ellinor, P T A1 - Evans, M K A1 - Ferrucci, L A1 - Fox, E R A1 - Heckbert, S R A1 - Heiss, G A1 - Hsueh, W C A1 - Kerr, K F A1 - Limacher, M C A1 - Liu, Y A1 - Lubitz, S A A1 - Magnani, J W A1 - Mehra, R A1 - Marcus, G M A1 - Murray, S S A1 - Newman, A B A1 - Njajou, O A1 - North, K E A1 - Paltoo, D N A1 - Psaty, B M A1 - Redline, S S A1 - Reiner, A P A1 - Robinson, J G A1 - Rotter, J I A1 - Samdarshi, T E A1 - Schnabel, R B A1 - Schork, N J A1 - Singleton, A B A1 - Siscovick, D A1 - Soliman, E Z A1 - Sotoodehnia, N A1 - Srinivasan, S R A1 - Taylor, H A A1 - Trevisan, M A1 - Zhang, Z A1 - Zonderman, A B A1 - Newton-Cheh, C A1 - Whitsel, E A KW - Adult KW - African Americans KW - Aged KW - Arrhythmias, Cardiac KW - Connexin 43 KW - Electrocardiography KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Heart Rate KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Rest KW - United States AB -

BACKGROUND: 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.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23183192?dopt=Abstract ER - TY - JOUR T1 - Common variants associated with plasma triglycerides and risk for coronary artery disease. JF - Nat Genet Y1 - 2013 A1 - Do, Ron A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Gao, Chi A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Eyjolfsson, Gudmundur Ingi A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Altshuler, David A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R A1 - Daly, Mark J A1 - Neale, Benjamin M A1 - Kathiresan, Sekar KW - Biological Transport KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Triglycerides AB -

Triglycerides 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.

VL - 45 IS - 11 ER - TY - JOUR T1 - Common variants in Mendelian kidney disease genes and their association with renal function. JF - J Am Soc Nephrol Y1 - 2013 A1 - Parsa, Afshin A1 - Fuchsberger, Christian A1 - Köttgen, Anna A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - de Andrade, Mariza A1 - Chasman, Daniel I A1 - Teumer, Alexander A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Kim, Young J A1 - Taliun, Daniel A1 - Li, Man A1 - Feitosa, Mary A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Rao, Madhumathi A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Couraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Hofer, Edith A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Kao, W Linda A1 - Böger, Carsten A KW - Databases, Genetic KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Mendelian Randomization Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic AB -

Many 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.

VL - 24 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract ER - TY - JOUR T1 - Cystatin C versus creatinine in determining risk based on kidney function. JF - N Engl J Med Y1 - 2013 A1 - Shlipak, Michael G A1 - Matsushita, Kunihiro A1 - Arnlöv, Johan A1 - Inker, Lesley A A1 - Katz, Ronit A1 - Polkinghorne, Kevan R A1 - Rothenbacher, Dietrich A1 - Sarnak, Mark J A1 - Astor, Brad C A1 - Coresh, Josef A1 - Levey, Andrew S A1 - Gansevoort, Ron T KW - Creatinine KW - Cystatin C KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Kidney Function Tests KW - Reference Standards KW - Renal Insufficiency, Chronic KW - Risk KW - Risk Assessment AB -

BACKGROUND: 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.).

VL - 369 IS - 10 ER - TY - JOUR T1 - Discovery and refinement of loci associated with lipid levels. JF - Nat Genet Y1 - 2013 A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Do, Ron A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Ingi Eyjolfsson, Gudmundur A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Kathiresan, Sekar A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R KW - African Continental Ancestry Group KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipids KW - Triglycerides AB -

Levels 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.

VL - 45 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract ER - TY - JOUR T1 - Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - North, Kari E A1 - Lim, Unhee A1 - Bůzková, Petra A1 - Crawford, Dana C A1 - Haessler, Jeffrey A1 - Gross, Myron D A1 - Fowke, Jay H A1 - Goodloe, Robert A1 - Love, Shelley-Ann A1 - Graff, Misa A1 - Carlson, Christopher S A1 - Kuller, Lewis H A1 - Matise, Tara C A1 - Hong, Ching-Ping A1 - Henderson, Brian E A1 - Allen, Melissa A1 - Rohde, Rebecca R A1 - Mayo, Ping A1 - Schnetz-Boutaud, Nathalie A1 - Monroe, Kristine R A1 - Ritchie, Marylyn D A1 - Prentice, Ross L A1 - Kolonel, Lawrence N A1 - Manson, JoAnn E A1 - Pankow, James A1 - Hindorff, Lucia A A1 - Franceschini, Nora A1 - Wilkens, Lynne R A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Peters, Ulrike KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Membrane Proteins KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - Risk Factors KW - Smoking KW - Young Adult AB -

BACKGROUND: 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.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23311614?dopt=Abstract ER - TY - JOUR T1 - Fine Mapping and Identification of BMI Loci in African Americans. JF - Am J Hum Genet Y1 - 2013 A1 - Gong, Jian A1 - Schumacher, Fredrick A1 - Lim, Unhee A1 - Hindorff, Lucia A A1 - Haessler, Jeff A1 - Buyske, Steven A1 - Carlson, Christopher S A1 - Rosse, Stephanie A1 - Bůzková, Petra A1 - Fornage, Myriam A1 - Gross, Myron A1 - Pankratz, Nathan A1 - Pankow, James S A1 - Schreiner, Pamela J A1 - Cooper, Richard A1 - Ehret, Georg A1 - Gu, C Charles A1 - Houston, Denise A1 - Irvin, Marguerite R A1 - Jackson, Rebecca A1 - Kuller, Lew A1 - Henderson, Brian A1 - Cheng, Iona A1 - Wilkens, Lynne A1 - Leppert, Mark A1 - Lewis, Cora E A1 - Li, Rongling A1 - Nguyen, Khanh-Dung H A1 - Goodloe, Robert A1 - Farber-Eger, Eric A1 - Boston, Jonathan A1 - Dilks, Holli H A1 - Ritchie, Marylyn D A1 - Fowke, Jay A1 - Pooler, Loreall A1 - Graff, Misa A1 - Fernandez-Rhodes, Lindsay A1 - Cochrane, Barbara A1 - Boerwinkle, Eric A1 - Kooperberg, Charles A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - North, Kari E A1 - Peters, Ulrike KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Genome-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.

VL - 93 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24094743?dopt=Abstract ER - TY - JOUR T1 - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. JF - PLoS Biol Y1 - 2013 A1 - Carlson, Christopher S A1 - Matise, Tara C A1 - North, Kari E A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Buyske, Steven A1 - Schumacher, Fredrick R A1 - Peters, Ulrike A1 - Franceschini, Nora A1 - Ritchie, Marylyn D A1 - Duggan, David J A1 - Spencer, Kylee L A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Thomas, Fridtjof A1 - Young, Alicia A1 - Carty, Cara A1 - Heiss, Gerardo A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Kooperberg, Charles L KW - African Americans KW - Asian Americans KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Lipids KW - Metagenomics KW - Oceanic Ancestry Group KW - Polymorphism, Single Nucleotide AB -

The 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.

VL - 11 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract ER - TY - JOUR T1 - Genetic analysis of a population heavy drinking phenotype identifies risk variants in whites. JF - J Clin Psychopharmacol Y1 - 2013 A1 - Hamidovic, Ajna A1 - Goodloe, Robert J A1 - Young, Taylor R A1 - Styn, Mindi A A1 - Mukamal, Kenneth J A1 - Choquet, Helene A1 - Kasberger, Jay L A1 - Buxbaum, Sarah G A1 - Papanicolaou, George J A1 - White, Wendy A1 - Volcik, Kelly A1 - Spring, Bonnie A1 - Hitsman, Brian A1 - Levy, Daniel A1 - Jorgenson, Eric KW - Aged KW - Alcohol Drinking KW - Alcoholism KW - Case-Control Studies KW - European Continental Ancestry Group KW - Feasibility Studies KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk AB -

Genetic 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.

VL - 33 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23422394?dopt=Abstract ER - TY - JOUR T1 - Genetic loci for retinal arteriolar microcirculation. JF - PLoS One Y1 - 2013 A1 - Sim, Xueling A1 - Jensen, Richard A A1 - Ikram, M Kamran A1 - Cotch, Mary Frances A1 - Li, Xiaohui A1 - Macgregor, Stuart A1 - Xie, Jing A1 - Smith, Albert Vernon A1 - Boerwinkle, Eric A1 - Mitchell, Paul A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - de Jong, Paulus T V M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Jonasson, Fridbert A1 - Launer, Lenore J A1 - Attia, John A1 - Baird, Paul N A1 - Harrap, Stephen A1 - Holliday, Elizabeth G A1 - Inouye, Michael A1 - Rochtchina, Elena A1 - Scott, Rodney J A1 - Viswanathan, Ananth A1 - Li, Guo A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Kuo, Jane Z A1 - Taylor, Kent D A1 - Hewitt, Alex W A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Sun, Cong A1 - Young, Terri L A1 - Mackey, David A A1 - van Zuydam, Natalie R A1 - Doney, Alex S F A1 - Palmer, Colin N A A1 - Morris, Andrew D A1 - Rotter, Jerome I A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Vingerling, Johannes R A1 - Siscovick, David S A1 - Wang, Jie Jin A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Arterioles KW - Chromosomes, Human, Pair 5 KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - MEF2 Transcription Factors KW - Microcirculation KW - Middle Aged KW - Models, Genetic KW - Retinal Vessels AB -

Narrow 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.

VL - 8 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. JF - Obesity (Silver Spring) Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - North, Kari E A1 - Ritchie, Marylyn D A1 - Lim, Unhee A1 - Franceschini, Nora A1 - Wilkens, Lynne R A1 - Gross, Myron D A1 - Bůzková, Petra A1 - Glenn, Kimberly A1 - Quibrera, P Miguel A1 - Fernandez-Rhodes, Lindsay A1 - Li, Qiong A1 - Fowke, Jay H A1 - Li, Rongling A1 - Carlson, Christopher S A1 - Prentice, Ross L A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Matise, Tara C A1 - Cole, Shelley A A1 - Chen, Christina T L A1 - Howard, Barbara V A1 - Kolonel, Laurence N A1 - Henderson, Brian E A1 - Monroe, Kristine R A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Buyske, Steven A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Peters, Ulrike KW - Alleles KW - Body Mass Index KW - Ethnic Groups KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Metagenomics KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

OBJECTIVE: 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.

VL - 21 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23712987?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - Meigs, James B A1 - North, Kari E A1 - Schumacher, Fredrick R A1 - Bůzková, Petra A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Goodloe, Robert A1 - Spencer, Kylee L A1 - Voruganti, Venkata Saroja A1 - Howard, Barbara V A1 - Jackson, Rebecca A1 - Kolonel, Laurence N A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Monroe, Kristine R A1 - Mukamal, Kenneth A1 - Dilks, Holli H A1 - Pendergrass, Sarah A A1 - Nato, Andrew A1 - Wan, Peggy A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Florez, Jose C A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Pankow, James S KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomics KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: 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.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24063630?dopt=Abstract ER - TY - JOUR T1 - Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study. JF - Diabetes Care Y1 - 2013 A1 - Jensen, Majken K A1 - Bartz, Traci M A1 - Djoussé, Luc A1 - Kizer, Jorge R A1 - Zieman, Susan J A1 - Rimm, Eric B A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Ix, Joachim H A1 - Mukamal, Kenneth J KW - alpha-2-HS-Glycoprotein KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Genotype KW - Humans KW - Male KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE: 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.

VL - 36 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23801724?dopt=Abstract ER - TY - JOUR T1 - Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. JF - Hum Mol Genet Y1 - 2013 A1 - Reiner, Alexander P A1 - Hartiala, Jaana A1 - Zeller, Tanja A1 - Bis, Joshua C A1 - Dupuis, Josée A1 - Fornage, Myriam A1 - Baumert, Jens A1 - Kleber, Marcus E A1 - Wild, Philipp S A1 - Baldus, Stephan A1 - Bielinski, Suzette J A1 - Fontes, João D A1 - Illig, Thomas A1 - Keating, Brendan J A1 - Lange, Leslie A A1 - Ojeda, Francisco A1 - Müller-Nurasyid, Martina A1 - Munzel, Thomas F A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Tang, W H Wilson A1 - Thorand, Barbara A1 - Erdmann, Jeanette A1 - Jacobs, David R A1 - Wilson, James G A1 - Koenig, Wolfgang A1 - Tracy, Russell P A1 - Blankenberg, Stefan A1 - März, Winfried A1 - Gross, Myron D A1 - Benjamin, Emelia J A1 - Hazen, Stanley L A1 - Allayee, Hooman KW - Adult KW - African Americans KW - Aged KW - Case-Control Studies KW - Complement Factor H KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Gene Expression Regulation, Enzymologic KW - Genetic Association Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Peroxidase KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Increased 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.

VL - 22 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23620142?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Asa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - D'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

Elevated 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.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association of body fat distribution in African ancestry populations suggests new loci. JF - PLoS Genet Y1 - 2013 A1 - Liu, Ching-Ti A1 - Monda, Keri L A1 - Taylor, Kira C A1 - Lange, Leslie A1 - Demerath, Ellen W A1 - Palmas, Walter A1 - Wojczynski, Mary K A1 - Ellis, Jaclyn C A1 - Vitolins, Mara Z A1 - Liu, Simin A1 - Papanicolaou, George J A1 - Irvin, Marguerite R A1 - Xue, Luting A1 - Griffin, Paula J A1 - Nalls, Michael A A1 - Adeyemo, Adebowale A1 - Liu, Jiankang A1 - Li, Guo A1 - Ruiz-Narvaez, Edward A A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Henderson, Brian E A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - Strom, Sara S A1 - Guo, Xiuqing A1 - Andrews, Jeanette S A1 - Sun, Yan V A1 - Mosley, Thomas H A1 - Yanek, Lisa R A1 - Shriner, Daniel A1 - Haritunians, Talin A1 - Rotter, Jerome I A1 - Speliotes, Elizabeth K A1 - Smith, Megan A1 - Rosenberg, Lynn A1 - Mychaleckyj, Josyf A1 - Nayak, Uma A1 - Spruill, Ida A1 - Garvey, W Timothy A1 - Pettaway, Curtis A1 - Nyante, Sarah A1 - Bandera, Elisa V A1 - Britton, Angela F A1 - Zonderman, Alan B A1 - Rasmussen-Torvik, Laura J A1 - Chen, Yii-Der Ida A1 - Ding, Jingzhong A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Zhao, Wei A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Kabagambe, Edmond A1 - Broeckel, Ulrich A1 - Chen, Guanjie A1 - Zhou, Jie A1 - Wassertheil-Smoller, Sylvia A1 - Neuhouser, Marian L A1 - Rampersaud, Evadnie A1 - Psaty, Bruce A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Kuller, Lewis H A1 - Ochs-Balcom, Heather M A1 - Johnson, Karen C A1 - Sucheston, Lara A1 - Ordovas, Jose M A1 - Palmer, Julie R A1 - Haiman, Christopher A A1 - McKnight, Barbara A1 - Howard, Barbara V A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Liu, Yongmei A1 - Allison, Matthew A A1 - Grant, Struan F A A1 - Burke, Gregory L A1 - Patel, Sanjay R A1 - Schreiner, Pamela J A1 - Borecki, Ingrid B A1 - Evans, Michele K A1 - Taylor, Herman A1 - Sale, Michèle M A1 - Howard, Virginia A1 - Carlson, Christopher S A1 - Rotimi, Charles N A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Reiner, Alexander P A1 - Cupples, L Adrienne A1 - North, Kari E A1 - Fox, Caroline S KW - Adiposity KW - African Continental Ancestry Group KW - Body Fat Distribution KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Central 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.

VL - 9 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. JF - Genet Epidemiol Y1 - 2013 A1 - Tang, Weihong A1 - Teichert, Martina A1 - Chasman, Daniel I A1 - Heit, John A A1 - Morange, Pierre-Emmanuel A1 - Li, Guo A1 - Pankratz, Nathan A1 - Leebeek, Frank W A1 - Paré, Guillaume A1 - de Andrade, Mariza A1 - Tzourio, Christophe A1 - Psaty, Bruce M A1 - Basu, Saonli A1 - Ruiter, Rikje A1 - Rose, Lynda A1 - Armasu, Sebastian M A1 - Lumley, Thomas A1 - Heckbert, Susan R A1 - Uitterlinden, André G A1 - Lathrop, Mark A1 - Rice, Kenneth M A1 - Cushman, Mary A1 - Hofman, Albert A1 - Lambert, Jean-Charles A1 - Glazer, Nicole L A1 - Pankow, James S A1 - Witteman, Jacqueline C A1 - Amouyel, Philippe A1 - Bis, Joshua C A1 - Bovill, Edwin G A1 - Kong, Xiaoxiao A1 - Tracy, Russell P A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Trégouët, David-Alexandre A1 - Loth, Daan W A1 - Stricker, Bruno H Ch A1 - Ridker, Paul M A1 - Folsom, Aaron R A1 - Smith, Nicholas L KW - Aged KW - Aging KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - Venous Thromboembolism AB -

Venous 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.

VL - 37 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23650146?dopt=Abstract ER - TY - JOUR T1 - Genome-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) consortiu JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Wu, Jason H Y A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - Guan, Weihua A1 - Tanaka, Toshiko A1 - Foy, Millennia A1 - Kabagambe, Edmond K A1 - Djoussé, Luc A1 - Siscovick, David A1 - Fretts, Amanda M A1 - Johnson, Catherine A1 - King, Irena B A1 - Psaty, Bruce M A1 - McKnight, Barbara A1 - Rich, Stephen S A1 - Chen, Yii-der I A1 - Nettleton, Jennifer A A1 - Tang, Weihong A1 - Bandinelli, Stefania A1 - Jacobs, David R A1 - Browning, Brian L A1 - Laurie, Cathy C A1 - Gu, Xiangjun A1 - Tsai, Michael Y A1 - Steffen, Lyn M A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Mozaffarian, Dariush KW - Adult KW - Aged KW - Chromosomes, Human, Pair 2 KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Fatty Acids, Monounsaturated KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Lipogenesis KW - Male KW - Middle Aged KW - Oleic Acid KW - Palmitic Acid KW - Polymorphism, Single Nucleotide KW - Stearic Acids AB -

BACKGROUND- 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.

VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23362303?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Fox, Ervin R A1 - Musani, Solomon K A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Yu, Bing A1 - Ogunyankin, Kofo O A1 - Smith, Nicholas L A1 - Kutlar, Abdullah A1 - Glazer, Nicole L A1 - Post, Wendy S A1 - Paltoo, Dina N A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Duarte, Christine W A1 - Kardia, Sharon L A1 - Meyers, Kristin J A1 - Sun, Yan V A1 - Arnett, Donna K A1 - Patki, Amit A A1 - Sha, Jin A1 - Cui, Xiangqui A1 - Samdarshi, Tandaw E A1 - Penman, Alan D A1 - Bibbins-Domingo, Kirsten A1 - Bůzková, Petra A1 - Benjamin, Emelia J A1 - Bluemke, David A A1 - Morrison, Alanna C A1 - Heiss, Gerardo A1 - Carr, J Jeffrey A1 - Tracy, Russell P A1 - Mosley, Thomas H A1 - Taylor, Herman A A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Cappola, Thomas P A1 - Vasan, Ramachandran S KW - African Americans KW - Aged KW - Cohort Studies KW - Diastole KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

BACKGROUND: 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.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of depressive symptoms. JF - Biol Psychiatry Y1 - 2013 A1 - Hek, Karin A1 - Demirkan, Ayse A1 - Lahti, Jari A1 - Terracciano, Antonio A1 - Teumer, Alexander A1 - Cornelis, Marilyn C A1 - Amin, Najaf A1 - Bakshis, Erin A1 - Baumert, Jens A1 - Ding, Jingzhong A1 - Liu, Yongmei A1 - Marciante, Kristin A1 - Meirelles, Osorio A1 - Nalls, Michael A A1 - Sun, Yan V A1 - Vogelzangs, Nicole A1 - Yu, Lei A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Bennett, David A A1 - Boomsma, Dorret A1 - Cannas, Alessandra A1 - Coker, Laura H A1 - de Geus, Eco A1 - De Jager, Philip L A1 - Diez-Roux, Ana V A1 - Purcell, Shaun A1 - Hu, Frank B A1 - Rimma, Eric B A1 - Hunter, David J A1 - Jensen, Majken K A1 - Curhan, Gary A1 - Rice, Kenneth A1 - Penman, Alan D A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Emeny, Rebecca A1 - Eriksson, Johan G A1 - Evans, Denis A A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Illig, Thomas A1 - Kardia, Sharon A1 - Kelly-Hayes, Margaret A1 - Koenen, Karestan A1 - Kraft, Peter A1 - Kuningas, Maris A1 - Massaro, Joseph M A1 - Melzer, David A1 - Mulas, Antonella A1 - Mulder, Cornelis L A1 - Murray, Anna A1 - Oostra, Ben A A1 - Palotie, Aarno A1 - Penninx, Brenda A1 - Petersmann, Astrid A1 - Pilling, Luke C A1 - Psaty, Bruce A1 - Rawal, Rajesh A1 - Reiman, Eric M A1 - Schulz, Andrea A1 - Shulman, Joshua M A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Sutin, Angelina R A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Widen, Elisabeth A1 - Yaffe, Kristine A1 - Zonderman, Alan B A1 - Cucca, Francesco A1 - Harris, Tamara A1 - Ladwig, Karl-Heinz A1 - Llewellyn, David J A1 - Räikkönen, Katri A1 - Tanaka, Toshiko A1 - van Duijn, Cornelia M A1 - Grabe, Hans J A1 - Launer, Lenore J A1 - Lunetta, Kathryn L A1 - Mosley, Thomas H A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Murabito, Joanne KW - Aged KW - Aged, 80 and over KW - Chromosomes, Human, Pair 5 KW - Depression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 73 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of early menopause and the combined impact of identified variants. JF - Hum Mol Genet Y1 - 2013 A1 - Perry, John R B A1 - Corre, Tanguy A1 - Esko, Tõnu A1 - Chasman, Daniel I A1 - Fischer, Krista A1 - Franceschini, Nora A1 - He, Chunyan A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Vernon Smith, Albert A1 - Stolk, Lisette A1 - Sulem, Patrick A1 - Weedon, Michael N A1 - Zhuang, Wei V A1 - Arnold, Alice A1 - Ashworth, Alan A1 - Bergmann, Sven A1 - Buring, Julie E A1 - Burri, Andrea A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Couper, David J A1 - Goodarzi, Mark O A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hofman, Albert A1 - Jones, Michael A1 - Kraft, Peter A1 - Launer, Lenore A1 - Laven, Joop S E A1 - Li, Guo A1 - McKnight, Barbara A1 - Masciullo, Corrado A1 - Milani, Lili A1 - Orr, Nicholas A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Schoemaker, Minouk A1 - Traglia, Michela A1 - Waeber, Gérard A1 - Chanock, Stephen J A1 - Demerath, Ellen W A1 - Garcia, Melissa A1 - Hankinson, Susan E A1 - Hu, Frank B A1 - Hunter, David J A1 - Lunetta, Kathryn L A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Ong, Ken K A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Swerdlow, Anthony J A1 - Thorsteinsdottir, Unnur A1 - van Dam, Rob M A1 - Uitterlinden, André G A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Toniolo, Daniela A1 - Murray, Anna KW - Case-Control Studies KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Menopause, Premature KW - Polymorphism, Single Nucleotide KW - Primary Ovarian Insufficiency KW - Quantitative Trait Loci KW - Risk AB -

Early 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.

VL - 22 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23307926?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of retinopathy in individuals without diabetes. JF - PLoS One Y1 - 2013 A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Li, Xiaohui A1 - Cotch, Mary Frances A1 - Ikram, M Kamran A1 - Holliday, Elizabeth G A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Jonasson, Fridbert A1 - Klein, Barbara E K A1 - Launer, Lenore J A1 - Smith, Albert Vernon A1 - Boerwinkle, Eric A1 - Cheung, Ning A1 - Hewitt, Alex W A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Wang, Jie Jin A1 - Attia, John A1 - Scott, Rodney A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Taylor, Kent A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Tay, Wan-Ting A1 - Teo, Yik Ying A1 - Seielstad, Mark A1 - Liu, Jianjun A1 - Cheng, Ching-Yu A1 - Saw, Seang-Mei A1 - Aung, Tin A1 - Ganesh, Santhi K A1 - O'Donnell, Christopher J A1 - Nalls, Mike A A1 - Wiggins, Kerri L A1 - Kuo, Jane Z A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Klein, Ronald A1 - Siscovick, David S A1 - Rotter, Jerome I A1 - Tai, E Shong A1 - Vingerling, Johannes A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Histone Deacetylases KW - Humans KW - Hypertension KW - Male KW - Polymorphism, Single Nucleotide KW - Repressor Proteins KW - Retinal Diseases AB -

BACKGROUND: 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.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23393555?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. JF - Nat Genet Y1 - 2013 A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Mägi, Reedik A1 - Ganna, Andrea A1 - Wheeler, Eleanor A1 - Feitosa, Mary F A1 - Justice, Anne E A1 - Monda, Keri L A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gentilini, Davide A1 - Jackson, Anne U A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Willer, Cristen J A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Hu, Yi-Juan A1 - Lee, Sang Hong A1 - Liang, Liming A1 - Lin, Dan-Yu A1 - Min, Josine L A1 - Neale, Benjamin M A1 - Thorleifsson, Gudmar A1 - Yang, Jian A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - den Heijer, Martin A1 - Eklund, Niina A1 - Fischer, Krista A1 - Goel, Anuj A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Jarick, Ivonne A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - König, Inke R A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lamina, Claudia A1 - Lecoeur, Cécile A1 - Li, Guo A1 - Mangino, Massimo A1 - McArdle, Wendy L A1 - Medina-Gómez, Carolina A1 - Müller-Nurasyid, Martina A1 - Ngwa, Julius S A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Pechlivanis, Sonali A1 - Perola, Markus A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Rose, Lynda M A1 - Shi, Jianxin A1 - Shungin, Dmitry A1 - Smith, Albert Vernon A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Trip, Mieke D A1 - Tyrer, Jonathan A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Waite, Lindsay L A1 - Zhao, Jing Hua A1 - Absher, Devin A1 - Asselbergs, Folkert W A1 - Atalay, Mustafa A1 - Attwood, Antony P A1 - Balmforth, Anthony J A1 - Basart, Hanneke A1 - Beilby, John A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Connell, John M A1 - Cookson, William O A1 - de Faire, Ulf A1 - de Vegt, Femmie A1 - Dei, Mariano A1 - Dimitriou, Maria A1 - Edkins, Sarah A1 - Estrada, Karol A1 - Evans, David M A1 - Farrall, Martin A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Franke, Lude A1 - Frau, Francesca A1 - Gejman, Pablo V A1 - Grallert, Harald A1 - Grönberg, Henrik A1 - Gudnason, Vilmundur A1 - Hall, Alistair S A1 - Hall, Per A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Heath, Andrew C A1 - Hebebrand, Johannes A1 - Homuth, Georg A1 - Hu, Frank B A1 - Hunt, Sarah E A1 - Hyppönen, Elina A1 - Iribarren, Carlos A1 - Jacobs, Kevin B A1 - Jansson, John-Olov A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Khaw, Kay-Tee A1 - Kivimaki, Mika A1 - Koenig, Wolfgang A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laitinen, Jaana H A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lind, Lars A1 - Lindström, Jaana A1 - Liu, Jianjun A1 - Liuzzi, Antonio A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Madden, Pamela A A1 - Magnusson, Patrik K A1 - Manunta, Paolo A1 - Marek, Diana A1 - März, Winfried A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Mooser, Vincent A1 - Mühleisen, Thomas W A1 - Munroe, Patricia B A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Navis, Gerjan A1 - Nicholson, George A1 - Nohr, Ellen A A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Palotie, Aarno A1 - Peden, John F A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Pütter, Carolin A1 - Radhakrishnan, Aparna A1 - Raitakari, Olli A1 - Rendon, Augusto A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Saaristo, Timo E A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Shin, So-Youn A1 - Signorini, Stefano A1 - Sinisalo, Juha A1 - Skrobek, Boris A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Stark, Klaus A1 - Stephens, Jonathan C A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Stumvoll, Michael A1 - Swift, Amy J A1 - Theodoraki, Eirini V A1 - Thorand, Barbara A1 - Trégouët, David-Alexandre A1 - Tremoli, Elena A1 - van der Klauw, Melanie M A1 - van Meurs, Joyce B J A1 - Vermeulen, Sita H A1 - Viikari, Jorma A1 - Virtamo, Jarmo A1 - Vitart, Veronique A1 - Waeber, Gérard A1 - Wang, Zhaoming A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Winkelmann, Bernhard R A1 - Witteman, Jacqueline C M A1 - Wolffenbuttel, Bruce H R A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Amouyel, Philippe A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Dedoussis, George V A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hingorani, Aroon A1 - Hinney, Anke A1 - Hofman, Albert A1 - Hovingh, Kees G A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Kuh, Diana A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Levinson, Douglas F A1 - Martin, Nicholas G A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nieminen, Markku S A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ouwehand, Willem H A1 - Palmer, Lyle J A1 - Penninx, Brenda A1 - Power, Chris A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Rauramaa, Rainer A1 - Ridker, Paul M A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Vollenweider, Peter A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunian, Talin A1 - Heid, Iris M A1 - Hunter, David A1 - Kaplan, Robert C A1 - Karpe, Fredrik A1 - Moffatt, Miriam F A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Pawitan, Yudi A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Steinthorsdottir, Valgerdur A1 - Strachan, David P A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Visscher, Peter M A1 - Di Blasio, Anna Maria A1 - Hirschhorn, Joel N A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Meyre, David A1 - Scherag, Andre A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Loos, Ruth J F A1 - Ingelsson, Erik KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Case-Control Studies KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Meta-Analysis as Topic KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Waist-Hip Ratio AB -

Approaches 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.

VL - 45 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract ER - TY - JOUR T1 - Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. JF - Hum Genet Y1 - 2013 A1 - Hansel, Nadia N A1 - Ruczinski, Ingo A1 - Rafaels, Nicholas A1 - Sin, Don D A1 - Daley, Denise A1 - Malinina, Alla A1 - Huang, Lili A1 - Sandford, Andrew A1 - Murray, Tanda A1 - Kim, Yoonhee A1 - Vergara, Candelaria A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Li, Guo A1 - Elliott, W Mark A1 - Aminuddin, Farzian A1 - Dupuis, Josée A1 - O'Connor, George T A1 - Doheny, Kimberly A1 - Scott, Alan F A1 - Boezen, H Marike A1 - Postma, Dirkje S A1 - Smolonska, Joanna A1 - Zanen, Pieter A1 - Mohamed Hoesein, Firdaus A A1 - de Koning, Harry J A1 - Crystal, Ronald G A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Silverman, Edwin A1 - Wan, Emily A1 - Vestbo, Jorgen A1 - Lomas, David A A1 - Connett, John A1 - Wise, Robert A A1 - Neptune, Enid R A1 - Mathias, Rasika A A1 - Paré, Peter D A1 - Beaty, Terri H A1 - Barnes, Kathleen C KW - Adult KW - Ankyrins KW - Chromosomes, Human, Pair 10 KW - Chromosomes, Human, Pair 14 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Hepatocyte Nuclear Factor 3-alpha KW - Humans KW - Linkage Disequilibrium KW - Lung KW - Male KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Pulmonary Disease, Chronic Obstructive AB -

Accelerated 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.

VL - 132 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22986903?dopt=Abstract ER - TY - JOUR T1 - Height and risk of incident intraparenchymal hemorrhage: Atherosclerosis Risk in Communities and Cardiovascular Health study cohorts. JF - J Stroke Cerebrovasc Dis Y1 - 2013 A1 - Smith, Lindsay G A1 - Yatsuya, Hiroshi A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Folsom, Aaron R KW - African Americans KW - Aged KW - Body Height KW - Cerebral Hemorrhage KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Time Factors KW - United States AB -

BACKGROUND: 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.

VL - 22 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22177930?dopt=Abstract ER - TY - JOUR T1 - Higher 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. JF - J Nutr Y1 - 2013 A1 - Hruby, Adela A1 - Ngwa, Julius S A1 - Renstrom, Frida A1 - Wojczynski, Mary K A1 - Ganna, Andrea A1 - Hallmans, Göran A1 - Houston, Denise K A1 - Jacques, Paul F A1 - Kanoni, Stavroula A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Sonestedt, Emily A1 - Tanaka, Toshiko A1 - van Rooij, Frank J A A1 - Bandinelli, Stefania A1 - Djoussé, Luc A1 - Grigoriou, Efi A1 - Johansson, Ingegerd A1 - Lohman, Kurt K A1 - Pankow, James S A1 - Raitakari, Olli T A1 - Riserus, Ulf A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Hassanali, Neelam A1 - Liu, Yongmei A1 - Mozaffarian, Dariush A1 - Papoutsakis, Constantina A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Viikari, Jorma A1 - Groves, Christopher J A1 - Hofman, Albert A1 - Lind, Lars A1 - McCarthy, Mark I A1 - Mikkilä, Vera A1 - Mukamal, Kenneth A1 - Franco, Oscar H A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Dedoussis, George V A1 - Ferrucci, Luigi A1 - Hu, Frank B A1 - Ingelsson, Erik A1 - Kähönen, Mika A1 - Kao, W H Linda A1 - Kritchevsky, Stephen B A1 - Orho-Melander, Marju A1 - Prokopenko, Inga A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Witteman, Jacqueline C M A1 - Franks, Paul W A1 - Meigs, James B A1 - McKeown, Nicola M A1 - Nettleton, Jennifer A KW - Blood Glucose KW - Female KW - Genetic Loci KW - Humans KW - Insulin KW - Magnesium KW - Male KW - Polymorphism, Single Nucleotide KW - Trace Elements KW - TRPM Cation Channels AB -

Favorable 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.

VL - 143 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23343670?dopt=Abstract ER - TY - JOUR T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. JF - Nat Genet Y1 - 2013 A1 - den Hoed, Marcel A1 - Eijgelsheim, Mark A1 - Esko, Tõnu A1 - Brundel, Bianca J J M A1 - Peal, David S A1 - Evans, David M A1 - Nolte, Ilja M A1 - Segrè, Ayellet V A1 - Holm, Hilma A1 - Handsaker, Robert E A1 - Westra, Harm-Jan A1 - Johnson, Toby A1 - Isaacs, Aaron A1 - Yang, Jian A1 - Lundby, Alicia A1 - Zhao, Jing Hua A1 - Kim, Young Jin A1 - Go, Min Jin A1 - Almgren, Peter A1 - Bochud, Murielle A1 - Boucher, Gabrielle A1 - Cornelis, Marilyn C A1 - Gudbjartsson, Daniel A1 - Hadley, David A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - den Heijer, Martin A1 - Igl, Wilmar A1 - Jackson, Anne U A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Kemp, John P A1 - Kristiansson, Kati A1 - Ladenvall, Claes A1 - Lorentzon, Mattias A1 - Montasser, May E A1 - Njajou, Omer T A1 - O'Reilly, Paul F A1 - Padmanabhan, Sandosh A1 - St Pourcain, Beate A1 - Rankinen, Tuomo A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - Timpson, Nicholas J A1 - Vitart, Veronique A1 - Waite, Lindsay A1 - Wheeler, William A1 - Zhang, Weihua A1 - Draisma, Harmen H M A1 - Feitosa, Mary F A1 - Kerr, Kathleen F A1 - Lind, Penelope A A1 - Mihailov, Evelin A1 - Onland-Moret, N Charlotte A1 - Song, Ci A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Yengo, Loic A1 - Absher, Devin A1 - Albert, Christine M A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - de Bakker, Paul I W A1 - Balkau, Beverley A1 - Barlassina, Cristina A1 - Benaglio, Paola A1 - Bis, Joshua C A1 - Bouatia-Naji, Nabila A1 - Brage, Søren A1 - Chanock, Stephen J A1 - Chines, Peter S A1 - Chung, Mina A1 - Darbar, Dawood A1 - Dina, Christian A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Felix, Stephan B A1 - Fischer, Krista A1 - Fuchsberger, Christian A1 - de Geus, Eco J C A1 - Goyette, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Hoogstra-Berends, Femke A1 - Hottenga, Jouke-Jan A1 - Jensen, Majken K A1 - Johansson, Asa A1 - Junttila, Juhani A1 - Kääb, Stefan A1 - Kanon, Bart A1 - Ketkar, Shamika A1 - Khaw, Kay-Tee A1 - Knowles, Joshua W A1 - Kooner, Angrad S A1 - Kors, Jan A A1 - Kumari, Meena A1 - Milani, Lili A1 - Laiho, Päivi A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Leusink, Maarten A1 - Liu, Yongmei A1 - Luben, Robert N A1 - Lunetta, Kathryn L A1 - Lynch, Stacey N A1 - Markus, Marcello R P A1 - Marques-Vidal, Pedro A1 - Mateo Leach, Irene A1 - McArdle, Wendy L A1 - McCarroll, Steven A A1 - Medland, Sarah E A1 - Miller, Kathryn A A1 - Montgomery, Grant W A1 - Morrison, Alanna C A1 - Müller-Nurasyid, Martina A1 - Navarro, Pau A1 - Nelis, Mari A1 - O'Connell, Jeffrey R A1 - O'Donnell, Christopher J A1 - Ong, Ken K A1 - Newman, Anne B A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Ring, Susan M A1 - Rossin, Elizabeth J A1 - Rudan, Diana A1 - Sanna, Serena A1 - Scott, Robert A A1 - Sehmi, Jaban S A1 - Sharp, Stephen A1 - Shin, Jordan T A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Stewart, Chip A1 - Stringham, Heather M A1 - Tarasov, Kirill V A1 - Uitterlinden, André G A1 - Vandenput, Liesbeth A1 - Hwang, Shih-Jen A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Wong, Andrew A1 - Wong, Quenna A1 - Jamshidi, Yalda A1 - Zitting, Paavo A1 - Boer, Jolanda M A A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Ekelund, Ulf A1 - Forouhi, Nita G A1 - Froguel, Philippe A1 - Hingorani, Aroon A1 - Ingelsson, Erik A1 - Kivimaki, Mika A1 - Kronmal, Richard A A1 - Kuh, Diana A1 - Lind, Lars A1 - Martin, Nicholas G A1 - Oostra, Ben A A1 - Pedersen, Nancy L A1 - Quertermous, Thomas A1 - Rotter, Jerome I A1 - van der Schouw, Yvonne T A1 - Verschuren, W M Monique A1 - Walker, Mark A1 - Albanes, Demetrius A1 - Arnar, David O A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Boehnke, Michael A1 - de Boer, Rudolf A A1 - Bouchard, Claude A1 - Caulfield, W L Mark A1 - Chambers, John C A1 - Curhan, Gary A1 - Cusi, Daniele A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - van Gilst, Wiek H A1 - Glorioso, Nicola A1 - de Graaf, Jacqueline A1 - Groop, Leif A1 - Gyllensten, Ulf A1 - Hsueh, Wen-Chi A1 - Hu, Frank B A1 - Huikuri, Heikki V A1 - Hunter, David J A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kiemeney, Lambertus A A1 - van der Klauw, Melanie M A1 - Kooner, Jaspal S A1 - Kraft, Peter A1 - Iacoviello, Licia A1 - Lehtimäki, Terho A1 - Lokki, Marja-Liisa L A1 - Mitchell, Braxton D A1 - Navis, Gerjan A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Poulter, Neil R A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rimm, Eric B A1 - Rioux, John D A1 - Rizzi, Federica A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Sever, Peter S A1 - Shields, Denis C A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stanton, Alice V A1 - Stolk, Ronald P A1 - Strachan, David P A1 - Tardif, Jean-Claude A1 - Thorsteinsdottir, Unnur A1 - Tuomilehto, Jaako A1 - van Veldhuisen, Dirk J A1 - Virtamo, Jarmo A1 - Viikari, Jorma A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Cho, Yoon Shin A1 - Olsen, Jesper V A1 - Visscher, Peter M A1 - Willer, Cristen A1 - Franke, Lude A1 - Erdmann, Jeanette A1 - Thompson, John R A1 - Pfeufer, Arne A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Ellinor, Patrick T A1 - Stricker, Bruno H Ch A1 - Metspalu, Andres A1 - Perola, Markus A1 - Beckmann, Jacques S A1 - Smith, George Davey A1 - Stefansson, Kari A1 - Wareham, Nicholas J A1 - Munroe, Patricia B A1 - Sibon, Ody C M A1 - Milan, David J A1 - Snieder, Harold A1 - Samani, Nilesh J A1 - Loos, Ruth J F KW - Animals KW - Arrhythmias, Cardiac KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Heart Rate KW - Humans KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Elevated 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.

VL - 45 IS - 6 ER - TY - JOUR T1 - The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study. JF - Diabetes Y1 - 2013 A1 - Graff, Mariaelisa A1 - Gordon-Larsen, Penny A1 - Lim, Unhee A1 - Fowke, Jay H A1 - Love, Shelly-Ann A1 - Fesinmeyer, Megan A1 - Wilkens, Lynne R A1 - Vertilus, Shawyntee A1 - Ritchie, Marilyn D A1 - Prentice, Ross L A1 - Pankow, Jim A1 - Monroe, Kristine A1 - Manson, JoAnn E A1 - Le Marchand, Loïc A1 - Kuller, Lewis H A1 - Kolonel, Laurence N A1 - Hong, Ching P A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Gross, Myron D A1 - Goodloe, Robert A1 - Franceschini, Nora A1 - Carlson, Christopher S A1 - Buyske, Steven A1 - Bůzková, Petra A1 - Hindorff, Lucia A A1 - Matise, Tara C A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - North, Kari E KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Health Surveys KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - United States KW - Young Adult AB -

Evidence 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.

VL - 62 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23300277?dopt=Abstract ER - TY - JOUR T1 - Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. JF - PLoS One Y1 - 2013 A1 - Holliday, Elizabeth G A1 - Smith, Albert V A1 - Cornes, Belinda K A1 - Buitendijk, Gabriëlle H S A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Aspelund, Thor A1 - Aung, Tin A1 - Baird, Paul N A1 - Boerwinkle, Eric A1 - Cheng, Ching Yu A1 - van Duijn, Cornelia M A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hewitt, Alex W A1 - Inouye, Michael A1 - Jonasson, Fridbert A1 - Klein, Barbara E K A1 - Launer, Lenore A1 - Li, Xiaohui A1 - Liew, Gerald A1 - Lumley, Thomas A1 - McElduff, Patrick A1 - McKnight, Barbara A1 - Mitchell, Paul A1 - Psaty, Bruce M A1 - Rochtchina, Elena A1 - Rotter, Jerome I A1 - Scott, Rodney J A1 - Tay, Wanting A1 - Taylor, Kent A1 - Teo, Yik Ying A1 - Uitterlinden, André G A1 - Viswanathan, Ananth A1 - Xie, Sophia A1 - Vingerling, Johannes R A1 - Klaver, Caroline C W A1 - Tai, E Shyong A1 - Siscovick, David A1 - Klein, Ronald A1 - Cotch, Mary Frances A1 - Wong, Tien Y A1 - Attia, John A1 - Wang, Jie Jin KW - Apolipoproteins E KW - Complement Factor H KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Kruppel-Like Transcription Factors KW - Macular Degeneration KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Proteins KW - Risk Factors KW - Zinc Finger Protein Gli3 AB -

Genetic 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.

VL - 8 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract ER - TY - JOUR T1 - Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. JF - BMC Genet Y1 - 2013 A1 - Taylor, Kira C A1 - Carty, Cara L A1 - Dumitrescu, Logan A1 - Bůzková, Petra A1 - Cole, Shelley A A1 - Hindorff, Lucia A1 - Schumacher, Fred R A1 - Wilkens, Lynne R A1 - Shohet, Ralph V A1 - Quibrera, P Miguel A1 - Johnson, Karen C A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Eaton, Charles B A1 - Duggan, David J A1 - Cochran, Barbara A1 - Cheng, Iona A1 - Carlson, Chris S A1 - Brown-Gentry, Kristin A1 - Anderson, Garnet A1 - Ambite, Jose Luis A1 - Haiman, Christopher A1 - Le Marchand, Loïc A1 - Kooperberg, Charles A1 - Crawford, Dana C A1 - Buyske, Steven A1 - North, Kari E A1 - Fornage, Myriam KW - Female KW - Genetic Heterogeneity KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Polymorphism, Single Nucleotide KW - Population Groups AB -

BACKGROUND: 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.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract ER - TY - JOUR T1 - Ischemic stroke is associated with the ABO locus: the EuroCLOT study. JF - Ann Neurol Y1 - 2013 A1 - Williams, Frances M K A1 - Carter, Angela M A1 - Hysi, Pirro G A1 - Surdulescu, Gabriela A1 - Hodgkiss, Dylan A1 - Soranzo, Nicole A1 - Traylor, Matthew A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M W A1 - Sudlow, Cathie A1 - Farrall, Martin A1 - Silander, Kaisa A1 - Kaunisto, Mari A1 - Wagner, Peter A1 - Saarela, Olli A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Salomaa, Veikko A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Ferrieres, Jean A1 - Wiklund, Per-Gunnar A1 - Ikram, M Arfan A1 - Hofman, Albert A1 - Boncoraglio, Giorgio B A1 - Parati, Eugenio A A1 - Helgadottir, Anna A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnur A1 - Thorleifsson, Gudmar A1 - Stefansson, Kari A1 - Seshadri, Sudha A1 - DeStefano, Anita A1 - Gschwendtner, Andreas A1 - Psaty, Bruce A1 - Longstreth, Will A1 - Mitchell, Braxton D A1 - Cheng, Yu-Ching A1 - Clarke, Robert A1 - Ferrario, Marco A1 - Bis, Joshua C A1 - Levi, Christopher A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Fornage, Myriam A1 - Sharma, Pankaj A1 - Furie, Karen L A1 - Rosand, Jonathan A1 - Nalls, Mike A1 - Meschia, James A1 - Mosely, Thomas H A1 - Evans, Alun A1 - Palotie, Aarno A1 - Markus, Hugh S A1 - Grant, Peter J A1 - Spector, Tim D KW - ABO Blood-Group System KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Coagulation KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Stroke KW - Young Adult AB -

OBJECTIVE: 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.

VL - 73 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. JF - Nat Genet Y1 - 2013 A1 - Monda, Keri L A1 - Chen, Gary K A1 - Taylor, Kira C A1 - Palmer, Cameron A1 - Edwards, Todd L A1 - Lange, Leslie A A1 - Ng, Maggie C Y A1 - Adeyemo, Adebowale A A1 - Allison, Matthew A A1 - Bielak, Lawrence F A1 - Chen, Guanjie A1 - Graff, Mariaelisa A1 - Irvin, Marguerite R A1 - Rhie, Suhn K A1 - Li, Guo A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Lu, Yingchang A1 - Nalls, Michael A A1 - Sun, Yan V A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Aldrich, Melinda C A1 - Ademola, Adeyinka A1 - Amos, Christopher I A1 - Bandera, Elisa V A1 - Bock, Cathryn H A1 - Britton, Angela A1 - Broeckel, Ulrich A1 - Cai, Quiyin A1 - Caporaso, Neil E A1 - Carlson, Chris S A1 - Carpten, John A1 - Casey, Graham A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Chen, Yii-der I A1 - Chiang, Charleston W K A1 - Coetzee, Gerhard A A1 - Demerath, Ellen A1 - Deming-Halverson, Sandra L A1 - Driver, Ryan W A1 - Dubbert, Patricia A1 - Feitosa, Mary F A1 - Feng, Ye A1 - Freedman, Barry I A1 - Gillanders, Elizabeth M A1 - Gottesman, Omri A1 - Guo, Xiuqing A1 - Haritunians, Talin A1 - Harris, Tamara A1 - Harris, Curtis C A1 - Hennis, Anselm J M A1 - Hernandez, Dena G A1 - McNeill, Lorna H A1 - Howard, Timothy D A1 - Howard, Barbara V A1 - Howard, Virginia J A1 - Johnson, Karen C A1 - Kang, Sun J A1 - Keating, Brendan J A1 - Kolb, Suzanne A1 - Kuller, Lewis H A1 - Kutlar, Abdullah A1 - Langefeld, Carl D A1 - Lettre, Guillaume A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lyon, Helen A1 - Manson, JoAnn E A1 - Maixner, William A1 - Meng, Yan A A1 - Monroe, Kristine R A1 - Morhason-Bello, Imran A1 - Murphy, Adam B A1 - Mychaleckyj, Josyf C A1 - Nadukuru, Rajiv A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Wu, Suh-Yuh A1 - Leske, M Cristina A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogunniyi, Adesola A1 - Ogundiran, Temidayo O A1 - Ojengbede, Oladosu A1 - Olopade, Olufunmilayo I A1 - Palmer, Julie R A1 - Ruiz-Narvaez, Edward A A1 - Palmer, Nicholette D A1 - Press, Michael F A1 - Rampersaud, Evandine A1 - Rasmussen-Torvik, Laura J A1 - Rodriguez-Gil, Jorge L A1 - Salako, Babatunde A1 - Schadt, Eric E A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Siscovick, David A1 - Smith, Shad B A1 - Wassertheil-Smoller, Sylvia A1 - Speliotes, Elizabeth K A1 - Spitz, Margaret R A1 - Sucheston, Lara A1 - Taylor, Herman A1 - Tayo, Bamidele O A1 - Tucker, Margaret A A1 - Van Den Berg, David J A1 - Edwards, Digna R Velez A1 - Wang, Zhaoming A1 - Wiencke, John K A1 - Winkler, Thomas W A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yang, James J A1 - Levin, Albert M A1 - Young, Taylor R A1 - Zakai, Neil A A1 - Cushman, Mary A1 - Zanetti, Krista A A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zheng, Yonglan A1 - Zhou, Jie A1 - Ziegler, Regina G A1 - Zmuda, Joseph M A1 - Fernandes, Jyotika K A1 - Gilkeson, Gary S A1 - Kamen, Diane L A1 - Hunt, Kelly J A1 - Spruill, Ida J A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Blot, William J A1 - Borecki, Ingrid B A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Burke, Gregory A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - Ding, Jingzhong A1 - Duggan, David A1 - Evans, Michele K A1 - Fox, Caroline A1 - Garvey, W Timothy A1 - Bradfield, Jonathan P A1 - Hakonarson, Hakon A1 - Grant, Struan F A A1 - Hsing, Ann A1 - Chu, Lisa A1 - Hu, Jennifer J A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - John, Esther M A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kardia, Sharon L R A1 - Kittles, Rick A A1 - Goodman, Phyllis J A1 - Klein, Eric A A1 - Kolonel, Laurence N A1 - Le Marchand, Loïc A1 - Liu, Simin A1 - McKnight, Barbara A1 - Millikan, Robert C A1 - Mosley, Thomas H A1 - Padhukasahasram, Badri A1 - Williams, L Keoki A1 - Patel, Sanjay R A1 - Peters, Ulrike A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotimi, Charles N A1 - Rybicki, Benjamin A A1 - Sale, Michèle M A1 - Schreiner, Pamela J A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Stanford, Janet L A1 - Strom, Sara S A1 - Thun, Michael J A1 - Vitolins, Mara A1 - Zheng, Wei A1 - Moore, Jason H A1 - Williams, Scott M A1 - Ketkar, Shamika A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Henderson, Brian E A1 - Reiner, Alex P A1 - Hirschhorn, Joel N A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A KW - African Americans KW - Body Mass Index KW - Case-Control Studies KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Genome-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.

VL - 45 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. JF - Nat Genet Y1 - 2013 A1 - Lambert, J C A1 - Ibrahim-Verbaas, C A A1 - Harold, D A1 - Naj, A C A1 - Sims, R A1 - Bellenguez, C A1 - DeStafano, A L A1 - Bis, J C A1 - Beecham, G W A1 - Grenier-Boley, B A1 - Russo, G A1 - Thorton-Wells, T A A1 - Jones, N A1 - Smith, A V A1 - Chouraki, V A1 - Thomas, C A1 - Ikram, M A A1 - Zelenika, D A1 - Vardarajan, B N A1 - Kamatani, Y A1 - Lin, C F A1 - Gerrish, A A1 - Schmidt, H A1 - Kunkle, B A1 - Dunstan, M L A1 - Ruiz, A A1 - Bihoreau, M T A1 - Choi, S H A1 - Reitz, C A1 - Pasquier, F A1 - Cruchaga, C A1 - Craig, D A1 - Amin, N A1 - Berr, C A1 - Lopez, O L A1 - De Jager, P L A1 - Deramecourt, V A1 - Johnston, J A A1 - Evans, D A1 - Lovestone, S A1 - Letenneur, L A1 - Morón, F J A1 - Rubinsztein, D C A1 - Eiriksdottir, G A1 - Sleegers, K A1 - Goate, A M A1 - Fiévet, N A1 - Huentelman, M W A1 - Gill, M A1 - Brown, K A1 - Kamboh, M I A1 - Keller, L A1 - Barberger-Gateau, P A1 - McGuiness, B A1 - Larson, E B A1 - Green, R A1 - Myers, A J A1 - Dufouil, C A1 - Todd, S A1 - Wallon, D A1 - Love, S A1 - Rogaeva, E A1 - Gallacher, J A1 - St George-Hyslop, P A1 - Clarimon, J A1 - Lleo, A A1 - Bayer, A A1 - Tsuang, D W A1 - Yu, L A1 - Tsolaki, M A1 - Bossù, P A1 - Spalletta, G A1 - Proitsi, P A1 - Collinge, J A1 - Sorbi, S A1 - Sanchez-Garcia, F A1 - Fox, N C A1 - Hardy, J A1 - Deniz Naranjo, M C A1 - Bosco, P A1 - Clarke, R A1 - Brayne, C A1 - Galimberti, D A1 - Mancuso, M A1 - Matthews, F A1 - Moebus, S A1 - Mecocci, P A1 - Del Zompo, M A1 - Maier, W A1 - Hampel, H A1 - Pilotto, A A1 - Bullido, M A1 - Panza, F A1 - Caffarra, P A1 - Nacmias, B A1 - Gilbert, J R A1 - Mayhaus, M A1 - Lannefelt, L A1 - Hakonarson, H A1 - Pichler, S A1 - Carrasquillo, M M A1 - Ingelsson, M A1 - Beekly, D A1 - Alvarez, V A1 - Zou, F A1 - Valladares, O A1 - Younkin, S G A1 - Coto, E A1 - Hamilton-Nelson, K L A1 - Gu, W A1 - Razquin, C A1 - Pastor, P A1 - Mateo, I A1 - Owen, M J A1 - Faber, K M A1 - Jonsson, P V A1 - Combarros, O A1 - O'Donovan, M C A1 - Cantwell, L B A1 - Soininen, H A1 - Blacker, D A1 - Mead, S A1 - Mosley, T H A1 - Bennett, D A A1 - Harris, T B A1 - Fratiglioni, L A1 - Holmes, C A1 - de Bruijn, R F A1 - Passmore, P A1 - Montine, T J A1 - Bettens, K A1 - Rotter, J I A1 - Brice, A A1 - Morgan, K A1 - Foroud, T M A1 - Kukull, W A A1 - Hannequin, D A1 - Powell, J F A1 - Nalls, M A A1 - Ritchie, K A1 - Lunetta, K L A1 - Kauwe, J S A1 - Boerwinkle, E A1 - Riemenschneider, M A1 - Boada, M A1 - Hiltuenen, M A1 - Martin, E R A1 - Schmidt, R A1 - Rujescu, D A1 - Wang, L S A1 - Dartigues, J F A1 - Mayeux, R A1 - Tzourio, C A1 - Hofman, A A1 - Nöthen, M M A1 - Graff, C A1 - Psaty, B M A1 - Jones, L A1 - Haines, J L A1 - Holmans, P A A1 - Lathrop, M A1 - Pericak-Vance, M A A1 - Launer, L J A1 - Farrer, L A A1 - van Duijn, C M A1 - Van Broeckhoven, C A1 - Moskvina, V A1 - Seshadri, S A1 - Williams, J A1 - Schellenberg, G D A1 - Amouyel, P KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Eleven 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.

VL - 45 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

Calcium 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.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. JF - PLoS Genet Y1 - 2013 A1 - Porcu, Eleonora A1 - Medici, Marco A1 - Pistis, Giorgio A1 - Volpato, Claudia B A1 - Wilson, Scott G A1 - Cappola, Anne R A1 - Bos, Steffan D A1 - Deelen, Joris A1 - den Heijer, Martin A1 - Freathy, Rachel M A1 - Lahti, Jari A1 - Liu, Chunyu A1 - Lopez, Lorna M A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Trompet, Stella A1 - Arnold, Alice A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Böhringer, Stefan A1 - Brown, Suzanne J A1 - Buckley, Brendan M A1 - Camaschella, Clara A1 - de Craen, Anton J M A1 - Davies, Gail A1 - de Visser, Marieke C H A1 - Ford, Ian A1 - Forsen, Tom A1 - Frayling, Timothy M A1 - Fugazzola, Laura A1 - Gögele, Martin A1 - Hattersley, Andrew T A1 - Hermus, Ad R A1 - Hofman, Albert A1 - Houwing-Duistermaat, Jeanine J A1 - Jensen, Richard A A1 - Kajantie, Eero A1 - Kloppenburg, Margreet A1 - Lim, Ee M A1 - Masciullo, Corrado A1 - Mariotti, Stefano A1 - Minelli, Cosetta A1 - Mitchell, Braxton D A1 - Nagaraja, Ramaiah A1 - Netea-Maier, Romana T A1 - Palotie, Aarno A1 - Persani, Luca A1 - Piras, Maria G A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Richards, J Brent A1 - Rivadeneira, Fernando A1 - Sala, Cinzia A1 - Sabra, Mona M A1 - Sattar, Naveed A1 - Shields, Beverley M A1 - Soranzo, Nicole A1 - Starr, John M A1 - Stott, David J A1 - Sweep, Fred C G J A1 - Usala, Gianluca A1 - van der Klauw, Melanie M A1 - van Heemst, Diana A1 - van Mullem, Alies A1 - Vermeulen, Sita H A1 - Visser, W Edward A1 - Walsh, John P A1 - Westendorp, Rudi G J A1 - Widen, Elisabeth A1 - Zhai, Guangju A1 - Cucca, Francesco A1 - Deary, Ian J A1 - Eriksson, Johan G A1 - Ferrucci, Luigi A1 - Fox, Caroline S A1 - Jukema, J Wouter A1 - Kiemeney, Lambertus A A1 - Pramstaller, Peter P A1 - Schlessinger, David A1 - Shuldiner, Alan R A1 - Slagboom, Eline P A1 - Uitterlinden, André G A1 - Vaidya, Bijay A1 - Visser, Theo J A1 - Wolffenbuttel, Bruce H R A1 - Meulenbelt, Ingrid A1 - Rotter, Jerome I A1 - Spector, Tim D A1 - Hicks, Andrew A A1 - Toniolo, Daniela A1 - Sanna, Serena A1 - Peeters, Robin P A1 - Naitza, Silvia KW - Female KW - Genome-Wide Association Study KW - Humans KW - Hyperthyroidism KW - Hypothyroidism KW - Male KW - Phenotype KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Signal Transduction KW - Thyroid Gland KW - Thyrotropin KW - Thyroxine AB -

Thyroid 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.

VL - 9 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23408906?dopt=Abstract ER - TY - JOUR T1 - Multiethnic 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. JF - Circulation Y1 - 2013 A1 - Sabater-Lleal, Maria A1 - Huang, Jie A1 - Chasman, Daniel A1 - Naitza, Silvia A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Teumer, Alexander A1 - Reiner, Alex P A1 - Folkersen, Lasse A1 - Basu, Saonli A1 - Rudnicka, Alicja R A1 - Trompet, Stella A1 - Mälarstig, Anders A1 - Baumert, Jens A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Hottenga, Jouke J A1 - Shin, So-Youn A1 - Lopez, Lorna M A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Oudot-Mellakh, Tiphaine A1 - Wilson, James F A1 - Navarro, Pau A1 - Huffman, Jennifer E A1 - Zemunik, Tatijana A1 - Redline, Susan A1 - Mehra, Reena A1 - Pulanic, Drazen A1 - Rudan, Igor A1 - Wright, Alan F A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Curb, J David A1 - Wallace, Robert A1 - Liu, Simin A1 - Eaton, Charles B A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Bandinelli, Stefania A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Fornage, Myriam A1 - Green, David A1 - Gross, Myron A1 - Davies, Gail A1 - Harris, Sarah E A1 - Liewald, David C A1 - Starr, John M A1 - Williams, Frances M K A1 - Grant, Peter J A1 - Spector, Timothy D A1 - Strawbridge, Rona J A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofman, Albert A1 - van Dongen, Jenny A1 - Willemsen, Gonneke A1 - Boomsma, Dorret I A1 - Yao, Jie A1 - Swords Jenny, Nancy A1 - Haritunians, Talin A1 - McKnight, Barbara A1 - Lumley, Thomas A1 - Taylor, Kent D A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Gieger, Christian A1 - Illig, Thomas A1 - Grotevendt, Anne A1 - Homuth, Georg A1 - Völzke, Henry A1 - Kocher, Thomas A1 - Goel, Anuj A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Clarke, Robert A1 - Steri, Maristella A1 - Tarasov, Kirill V A1 - Sanna, Serena A1 - Schlessinger, David A1 - Stott, David J A1 - Sattar, Naveed A1 - Buckley, Brendan M A1 - Rumley, Ann A1 - Lowe, Gordon D A1 - McArdle, Wendy L A1 - Chen, Ming-Huei A1 - Tofler, Geoffrey H A1 - Song, Jaejoon A1 - Boerwinkle, Eric A1 - Folsom, Aaron R A1 - Rose, Lynda M A1 - Franco-Cereceda, Anders A1 - Teichert, Martina A1 - Ikram, M Arfan A1 - Mosley, Thomas H A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M A1 - Sudlow, Cathie L M A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Kooner, Jaspal S A1 - Danesh, John A1 - Nelson, Christopher P A1 - Erdmann, Jeanette A1 - Reilly, Muredach P A1 - Kathiresan, Sekar A1 - Schunkert, Heribert A1 - Morange, Pierre-Emmanuel A1 - Ferrucci, Luigi A1 - Eriksson, Johan G A1 - Jacobs, David A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - de Geus, Eco J C A1 - Tracy, Russell P A1 - Hayward, Caroline A1 - Koenig, Wolfgang A1 - Cucca, Francesco A1 - Jukema, J Wouter A1 - Eriksson, Per A1 - Seshadri, Sudha A1 - Markus, Hugh S A1 - Watkins, Hugh A1 - Samani, Nilesh J A1 - Wallaschofski, Henri A1 - Smith, Nicholas L A1 - Tregouet, David A1 - Ridker, Paul M A1 - Tang, Weihong A1 - Strachan, David P A1 - Hamsten, Anders A1 - O'Donnell, Christopher J KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Venous Thromboembolism KW - Young Adult AB -

BACKGROUND: 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.

VL - 128 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract ER - TY - JOUR T1 - Racial differences in the incidence of and risk factors for atrial fibrillation in older adults: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2013 A1 - Jensen, Paul N A1 - Thacker, Evan L A1 - Dublin, Sascha A1 - Psaty, Bruce M A1 - Heckbert, Susan R KW - Aged KW - Atrial Fibrillation KW - Continental Population Groups KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Prevalence KW - Risk Assessment KW - Risk Factors KW - Stroke KW - United States AB -

This 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.

VL - 61 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23320758?dopt=Abstract ER - TY - JOUR T1 - Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. JF - Hum Reprod Y1 - 2013 A1 - Carty, C L A1 - Spencer, K L A1 - Setiawan, V W A1 - Fernandez-Rhodes, L A1 - Malinowski, J A1 - Buyske, S A1 - Young, A A1 - Jorgensen, N W A1 - Cheng, I A1 - Carlson, C S A1 - Brown-Gentry, K A1 - Goodloe, R A1 - Park, A A1 - Parikh, N I A1 - Henderson, B A1 - Le Marchand, L A1 - Wactawski-Wende, J A1 - Fornage, M A1 - Matise, T C A1 - Hindorff, L A A1 - Arnold, A M A1 - Haiman, C A A1 - Franceschini, N A1 - Peters, U A1 - Crawford, D C KW - Age Factors KW - Cross-Sectional Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Menarche KW - Menopause KW - Polymorphism, Single Nucleotide AB -

STUDY 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.

VL - 28 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23508249?dopt=Abstract ER - TY - JOUR T1 - Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study. JF - Circulation Y1 - 2013 A1 - Johnson, Andrew D A1 - Hwang, Shih-Jen A1 - Voorman, Arend A1 - Morrison, Alanna A1 - Peloso, Gina M A1 - Hsu, Yi-Hsiang A1 - Thanassoulis, George A1 - Newton-Cheh, Christopher A1 - Rogers, Ian S A1 - Hoffmann, Udo A1 - Freedman, Jane E A1 - Fox, Caroline S A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Cupples, L Adrienne A1 - O'Donnell, Christopher J KW - Calcinosis KW - Chromosomes, Human, Pair 9 KW - Coronary Artery Disease KW - Cyclin-Dependent Kinase Inhibitor p15 KW - Cyclin-Dependent Kinase Inhibitor p16 KW - DNA Copy Number Variations KW - Female KW - Follow-Up Studies KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Longitudinal Studies KW - Male KW - Massachusetts KW - Middle Aged KW - Myocardial Infarction KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - RNA, Long Noncoding KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 127 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23315372?dopt=Abstract ER - TY - JOUR T1 - Risk 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. JF - Eur J Epidemiol Y1 - 2013 A1 - Simone, Benedetto A1 - De Stefano, Valerio A1 - Leoncini, Emanuele A1 - Zacho, Jeppe A1 - Martinelli, Ida A1 - Emmerich, Joseph A1 - Rossi, Elena A1 - Folsom, Aaron R A1 - Almawi, Wassim Y A1 - Scarabin, Pierre Y A1 - den Heijer, Martin A1 - Cushman, Mary A1 - Penco, Silvana A1 - Vaya, Amparo A1 - Angchaisuksiri, Pantep A1 - Okumus, Gulfer A1 - Gemmati, Donato A1 - Cima, Simona A1 - Akar, Nejat A1 - Oguzulgen, Kivilcim I A1 - Ducros, Véronique A1 - Lichy, Christoph A1 - Fernandez-Miranda, Consuelo A1 - Szczeklik, Andrzej A1 - Nieto, José A A1 - Torres, Jose Domingo A1 - Le Cam-Duchez, Véronique A1 - Ivanov, Petar A1 - Cantu-Brito, Carlos A1 - Shmeleva, Veronika M A1 - Stegnar, Mojka A1 - Ogunyemi, Dotun A1 - Eid, Suhair S A1 - Nicolotti, Nicola A1 - De Feo, Emma A1 - Ricciardi, Walter A1 - Boccia, Stefania KW - Case-Control Studies KW - Factor V KW - Genetic Predisposition to Disease KW - Humans KW - Methylenetetrahydrofolate Reductase (NADPH2) KW - Prothrombin KW - Risk Factors KW - Venous Thromboembolism AB -

Genetic 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.

VL - 28 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23900608?dopt=Abstract ER - TY - JOUR T1 - Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. JF - PLoS Genet Y1 - 2013 A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Kutalik, Zoltán A1 - Berndt, Sonja I A1 - Jackson, Anne U A1 - Monda, Keri L A1 - Kilpeläinen, Tuomas O A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Li, Shengxu A1 - Workalemahu, Tsegaselassie A1 - Feitosa, Mary F A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Locke, Adam E A1 - Mathieson, Iain A1 - Scherag, Andre A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - Liang, Liming A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Dermitzakis, Emmanouil T A1 - Dimas, Antigone S A1 - Karpe, Fredrik A1 - Min, Josine L A1 - Nicholson, George A1 - Clegg, Deborah J A1 - Person, Thomas A1 - Krohn, Jon P A1 - Bauer, Sabrina A1 - Buechler, Christa A1 - Eisinger, Kristina A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Hottenga, Jouke-Jan A1 - Prokopenko, Inga A1 - Waite, Lindsay L A1 - Harris, Tamara B A1 - Smith, Albert Vernon A1 - Shuldiner, Alan R A1 - McArdle, Wendy L A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Grönberg, Henrik A1 - Chen, Yii-Der Ida A1 - Li, Guo A1 - Beckmann, Jacques S A1 - Johnson, Toby A1 - Thorsteinsdottir, Unnur A1 - Teder-Laving, Maris A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Oostra, Ben A A1 - Kraja, Aldi T A1 - Province, Michael A A1 - Cupples, L Adrienne A1 - Heard-Costa, Nancy L A1 - Kaprio, Jaakko A1 - Ripatti, Samuli A1 - Surakka, Ida A1 - Collins, Francis S A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Erdmann, Jeanette A1 - Hengstenberg, Christian A1 - Loley, Christina A1 - Schunkert, Heribert A1 - Lamina, Claudia A1 - Wichmann, H Erich A1 - Albrecht, Eva A1 - Gieger, Christian A1 - Hicks, Andrew A A1 - Johansson, Asa A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Speliotes, Elizabeth K A1 - Penninx, Brenda A1 - Hartikainen, Anna-Liisa A1 - Jarvelin, Marjo-Riitta A1 - Gyllensten, Ulf A1 - Boomsma, Dorret I A1 - Campbell, Harry A1 - Wilson, James F A1 - Chanock, Stephen J A1 - Farrall, Martin A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Rivadeneira, Fernando A1 - Estrada, Karol A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Zillikens, M Carola A1 - den Heijer, Martin A1 - Kiemeney, Lambertus A A1 - Maschio, Andrea A1 - Hall, Per A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Tönjes, Anke A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Attwood, Antony Paul A1 - Sambrook, Jennifer G A1 - Hung, Joseph A1 - Palmer, Lyle J A1 - Lokki, Marja-Liisa A1 - Sinisalo, Juha A1 - Boucher, Gabrielle A1 - Huikuri, Heikki A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Eklund, Niina A1 - Eriksson, Johan G A1 - Barlassina, Cristina A1 - Rivolta, Carlo A1 - Nolte, Ilja M A1 - Snieder, Harold A1 - van der Klauw, Melanie M A1 - van Vliet-Ostaptchouk, Jana V A1 - Gejman, Pablo V A1 - Shi, Jianxin A1 - Jacobs, Kevin B A1 - Wang, Zhaoming A1 - Bakker, Stephan J L A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van der Harst, Pim A1 - Martin, Nicholas G A1 - Medland, Sarah E A1 - Montgomery, Grant W A1 - Yang, Jian A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Raitakari, Olli A1 - Absher, Devin A1 - Iribarren, Carlos A1 - Basart, Hanneke A1 - Hovingh, Kees G A1 - Hyppönen, Elina A1 - Power, Chris A1 - Anderson, Denise A1 - Beilby, John P A1 - Hui, Jennie A1 - Jolley, Jennifer A1 - Sager, Hendrik A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Kristiansson, Kati A1 - Perola, Markus A1 - Lindström, Jaana A1 - Swift, Amy J A1 - Uusitupa, Matti A1 - Atalay, Mustafa A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Bolton, Jennifer L A1 - Fowkes, Gerry A1 - Fraser, Ross M A1 - Price, Jackie F A1 - Fischer, Krista A1 - Krjutå Kov, Kaarel A1 - Metspalu, Andres A1 - Mihailov, Evelin A1 - Langenberg, Claudia A1 - Luan, Jian'an A1 - Ong, Ken K A1 - Chines, Peter S A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Edkins, Sarah A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Shungin, Dmitry A1 - Morris, Andrew David A1 - Palmer, Colin N A A1 - Erbel, Raimund A1 - Moebus, Susanne A1 - Nöthen, Markus M A1 - Pechlivanis, Sonali A1 - Hveem, Kristian A1 - Narisu, Narisu A1 - Hamsten, Anders A1 - Humphries, Steve E A1 - Strawbridge, Rona J A1 - Tremoli, Elena A1 - Grallert, Harald A1 - Thorand, Barbara A1 - Illig, Thomas A1 - Koenig, Wolfgang A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Boehm, Bernhard O A1 - Kleber, Marcus E A1 - März, Winfried A1 - Winkelmann, Bernhard R A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Arveiler, Dominique A1 - Cesana, Giancarlo A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Yarnell, John W G A1 - Kuh, Diana A1 - Wong, Andrew A1 - Lind, Lars A1 - de Faire, Ulf A1 - Gigante, Bruna A1 - Magnusson, Patrik K E A1 - Pedersen, Nancy L A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Kolovou, Genovefa A1 - Kanoni, Stavroula A1 - Stirrups, Kathleen A1 - Bonnycastle, Lori L A1 - Njølstad, Inger A1 - Wilsgaard, Tom A1 - Ganna, Andrea A1 - Rehnberg, Emil A1 - Hingorani, Aroon A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David A1 - Ingelsson, Erik A1 - Kaplan, Robert A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Abecasis, Goncalo R A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Qi, Lu A1 - Loos, Ruth J F A1 - Lindgren, Cecilia M A1 - North, Kari E A1 - Heid, Iris M KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Body Weight KW - Body Weights and Measures KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist Circumference KW - Waist-Hip Ratio AB -

Given 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.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract ER - TY - JOUR T1 - Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. JF - J Am Heart Assoc Y1 - 2013 A1 - Alonso, Alvaro A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Stepas, Katherine A A1 - Pencina, Michael J A1 - Moser, Carlee B A1 - Sinner, Moritz F A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Ellinor, Patrick T A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Benjamin, Emelia J KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Iceland KW - Incidence KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Netherlands KW - Proportional Hazards Models KW - Risk Assessment KW - Smoking KW - United States AB -

BACKGROUND: 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.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract ER - TY - JOUR T1 - Strategy to control type I error increases power to identify genetic variation using the full biological trajectory. JF - Genet Epidemiol Y1 - 2013 A1 - Benke, K S A1 - Wu, Y A1 - Fallin, D M A1 - Maher, B A1 - Palmer, L J KW - Cohort Studies KW - Computer Simulation KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Linear Models KW - Models, Genetic KW - Polymorphism, Single Nucleotide AB -

Genome-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.

VL - 37 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23633177?dopt=Abstract ER - TY - JOUR T1 - A 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. JF - PLoS Genet Y1 - 2013 A1 - Peters, Ulrike A1 - North, Kari E A1 - Sethupathy, Praveen A1 - Buyske, Steve A1 - Haessler, Jeff A1 - Jiao, Shuo A1 - Fesinmeyer, Megan D A1 - Jackson, Rebecca D A1 - Kuller, Lew H A1 - Rajkovic, Aleksandar A1 - Lim, Unhee A1 - Cheng, Iona A1 - Schumacher, Fred A1 - Wilkens, Lynne A1 - Li, Rongling A1 - Monda, Keri A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Cooper, Richard A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Gu, C Charles A1 - Houston, Denise A1 - Bůzková, Petra A1 - Ritchie, Marylyn A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Hindorff, Lucia A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Kooperberg, Charles KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alleles KW - Body Mass Index KW - Chromosome Mapping KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Obesity KW - Proteins AB -

Genetic 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.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. JF - PLoS Genet Y1 - 2013 A1 - Wu, Ying A1 - Waite, Lindsay L A1 - Jackson, Anne U A1 - Sheu, Wayne H-H A1 - Buyske, Steven A1 - Absher, Devin A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Carty, Cara L A1 - Cheng, Iona A1 - Cochran, Barbara A1 - Croteau-Chonka, Damien C A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Henderson, Brian E A1 - Hindorff, Lucia A A1 - Kim, Eric A1 - Kinnunen, Leena A1 - Komulainen, Pirjo A1 - Lee, Wen-Jane A1 - Le Marchand, Loïc A1 - Lin, Yi A1 - Lindström, Jaana A1 - Lingaas-Holmen, Oddgeir A1 - Mitchell, Sabrina L A1 - Narisu, Narisu A1 - Robinson, Jennifer G A1 - Schumacher, Fred A1 - Stančáková, Alena A1 - Sundvall, Jouko A1 - Sung, Yun-Ju A1 - Swift, Amy J A1 - Wang, Wen-Chang A1 - Wilkens, Lynne A1 - Wilsgaard, Tom A1 - Young, Alicia M A1 - Adair, Linda S A1 - Ballantyne, Christie M A1 - Bůzková, Petra A1 - Chakravarti, Aravinda A1 - Collins, Francis S A1 - Duggan, David A1 - Feranil, Alan B A1 - Ho, Low-Tone A1 - Hung, Yi-Jen A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Juang, Jyh-Ming J A1 - Kesäniemi, Antero Y A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lee, I-Te A1 - Leppert, Mark F A1 - Matise, Tara C A1 - Moilanen, Leena A1 - Njølstad, Inger A1 - Peters, Ulrike A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rotter, Jerome I A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Wang, Tzung-Dau A1 - Boehnke, Michael A1 - Haiman, Christopher A A1 - Chen, Yii-der I A1 - Kooperberg, Charles A1 - Assimes, Themistocles L A1 - Crawford, Dana C A1 - Hsiung, Chao A A1 - North, Kari E A1 - Mohlke, Karen L KW - African Americans KW - Apolipoproteins A KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Proprotein Convertases KW - Serine Endopeptidases KW - Triglycerides AB -

Genome-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.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract ER - TY - JOUR T1 - Whole-genome sequence-based analysis of high-density lipoprotein cholesterol. JF - Nat Genet Y1 - 2013 A1 - Morrison, Alanna C A1 - Voorman, Arend A1 - Johnson, Andrew D A1 - Liu, Xiaoming A1 - Yu, Jin A1 - Li, Alexander A1 - Muzny, Donna A1 - Yu, Fuli A1 - Rice, Kenneth A1 - Zhu, Chengsong A1 - Bis, Joshua A1 - Heiss, Gerardo A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Gibbs, Richard A1 - Boerwinkle, Eric KW - Cholesterol, HDL KW - Computational Biology KW - Databases, Genetic KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Genomics KW - Heterozygote KW - Humans KW - Open Reading Frames AB -

We 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.

VL - 45 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23770607?dopt=Abstract ER - TY - JOUR T1 - ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - London, Stephanie J A1 - Gao, Wei A1 - Gharib, Sina A A1 - Hancock, Dana B A1 - Wilk, Jemma B A1 - House, John S A1 - Gibbs, Richard A A1 - Muzny, Donna M A1 - Lumley, Thomas A1 - Franceschini, Nora A1 - North, Kari E A1 - Psaty, Bruce M A1 - Kovar, Christie L A1 - Coresh, Josef A1 - Zhou, Yanhua A1 - Heckbert, Susan R A1 - Brody, Jennifer A A1 - Morrison, Alanna C A1 - Dupuis, Josée KW - ADAM Proteins KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951661?dopt=Abstract ER - TY - JOUR T1 - Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults. JF - Atherosclerosis Y1 - 2014 A1 - Kizer, Jorge R A1 - Benkeser, David A1 - Arnold, Alice M A1 - Ix, Joachim H A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Tracy, Russell P A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Zieman, Susan J KW - Aged KW - Albumins KW - Antihypertensive Agents KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Creatinine KW - Female KW - Glomerular Filtration Rate KW - Glycation End Products, Advanced KW - Humans KW - Immunoassay KW - Incidence KW - Lysine KW - Male KW - Oxidative Stress KW - Proportional Hazards Models KW - Stroke KW - Treatment Outcome AB -

BACKGROUND: 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.

VL - 235 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24825341?dopt=Abstract ER - TY - JOUR T1 - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. JF - BMJ Y1 - 2014 A1 - Holmes, Michael V A1 - Dale, Caroline E A1 - Zuccolo, Luisa A1 - Silverwood, Richard J A1 - Guo, Yiran A1 - Ye, Zheng A1 - Prieto-Merino, David A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Wong, Andrew A1 - Cavadino, Alana A1 - Drogan, Dagmar A1 - Padmanabhan, Sandosh A1 - Li, Shanshan A1 - Yesupriya, Ajay A1 - Leusink, Maarten A1 - Sundström, Johan A1 - Hubacek, Jaroslav A A1 - Pikhart, Hynek A1 - Swerdlow, Daniel I A1 - Panayiotou, Andrie G A1 - Borinskaya, Svetlana A A1 - Finan, Chris A1 - Shah, Sonia A1 - Kuchenbaecker, Karoline B A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Folkersen, Lasse A1 - Eriksson, Per A1 - Ricceri, Fulvio A1 - Melander, Olle A1 - Sacerdote, Carlotta A1 - Gamble, Dale M A1 - Rayaprolu, Sruti A1 - Ross, Owen A A1 - McLachlan, Stela A1 - Vikhireva, Olga A1 - Sluijs, Ivonne A1 - Scott, Robert A A1 - Adamkova, Vera A1 - Flicker, Leon A1 - Bockxmeer, Frank M van A1 - Power, Christine A1 - Marques-Vidal, Pedro A1 - Meade, Tom A1 - Marmot, Michael G A1 - Ferro, Jose M A1 - Paulos-Pinheiro, Sofia A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Mateo Leach, Irene A1 - Verweij, Niek A1 - Linneberg, Allan A1 - Skaaby, Tea A1 - Doevendans, Pieter A A1 - Cramer, Maarten J A1 - van der Harst, Pim A1 - Klungel, Olaf H A1 - Dowling, Nicole F A1 - Dominiczak, Anna F A1 - Kumari, Meena A1 - Nicolaides, Andrew N A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Ebrahim, Shah A1 - Gaunt, Tom R A1 - Price, Jackie F A1 - Lannfelt, Lars A1 - Peasey, Anne A1 - Kubinova, Ruzena A1 - Pajak, Andrzej A1 - Malyutina, Sofia A1 - Voevoda, Mikhail I A1 - Tamosiunas, Abdonas A1 - Maitland-van der Zee, Anke H A1 - Norman, Paul E A1 - Hankey, Graeme J A1 - Bergmann, Manuela M A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cooper, Jackie A1 - Palmen, Jutta A1 - Spiering, Wilko A1 - de Jong, Pim A A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Ford, Ian A1 - Hyppönen, Elina A1 - Almeida, Osvaldo P A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Hamsten, Anders A1 - Husemoen, Lise Lotte N A1 - Tjønneland, Anne A1 - Tolstrup, Janne S A1 - Rimm, Eric A1 - Beulens, Joline W J A1 - Verschuren, W M Monique A1 - Onland-Moret, N Charlotte A1 - Hofker, Marten H A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Morris, Richard A1 - Vicente, Astrid M A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Jukema, J Wouter A1 - Meschia, James A1 - Cupples, L Adrienne A1 - Sharp, Stephen J A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - LaCroix, Andrea Z A1 - Dai, James Y A1 - Lanktree, Matthew B A1 - Siscovick, David S A1 - Jorgenson, Eric A1 - Spring, Bonnie A1 - Coresh, Josef A1 - Li, Yun R A1 - Buxbaum, Sarah G A1 - Schreiner, Pamela J A1 - Ellison, R Curtis A1 - Tsai, Michael Y A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Johnson, Andrew D A1 - Hoogeveen, Ron C A1 - Hakonarson, Hakon A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - de Bakker, Paul I W A1 - Kivimaki, Mika A1 - Asselbergs, Folkert W A1 - Sattar, Naveed A1 - Lawlor, Debbie A A1 - Whittaker, John A1 - Davey Smith, George A1 - Mukamal, Kenneth A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Lange, Leslie A A1 - Hamidovic, Ajna A1 - Hingorani, Aroon D A1 - Nordestgaard, Børge G A1 - Bobak, Martin A1 - Leon, David A A1 - Langenberg, Claudia A1 - Palmer, Tom M A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Dudbridge, Frank A1 - Casas, Juan P KW - Adult KW - Aged KW - Alcohol Dehydrogenase KW - Alcohol Drinking KW - Biomarkers KW - Coronary Disease KW - Female KW - Genetic Markers KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Statistical KW - Polymorphism, Single Nucleotide KW - Stroke AB -

OBJECTIVE: 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.

VL - 349 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract ER - TY - JOUR T1 - Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis. JF - Arterioscler Thromb Vasc Biol Y1 - 2014 A1 - Ageno, Walter A1 - Di Minno, Matteo N D A1 - Ay, Cihan A1 - Jang, Moon Ju A1 - Hansen, John-Bjarne A1 - Steffen, Lyn M A1 - Vaya, Amparo A1 - Rattazzi, Marcello A1 - Pabinger, Ingrid A1 - Oh, Doyeun A1 - Di Minno, Giovanni A1 - Braekkan, Sigrid K A1 - Cushman, Mary A1 - Bonet, Elena A1 - Pauletto, Paolo A1 - Squizzato, Alessandro A1 - Dentali, Francesco KW - Adult KW - Aged KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Humans KW - Logistic Models KW - Male KW - Metabolic Syndrome KW - Middle Aged KW - Obesity, Abdominal KW - Risk Factors KW - Venous Thromboembolism AB -

OBJECTIVE: 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.

VL - 34 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25212233?dopt=Abstract ER - TY - JOUR T1 - Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts. JF - Stroke Y1 - 2014 A1 - Mahmoodi, Bakhtawar K A1 - Yatsuya, Hiroshi A1 - Matsushita, Kunihiro A1 - Sang, Yinying A1 - Gottesman, Rebecca F A1 - Astor, Brad C A1 - Woodward, Mark A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Shlipak, Michael G A1 - Folsom, Aaron R A1 - Gansevoort, Ron T A1 - Coresh, Josef KW - Aged KW - Albuminuria KW - Brain Ischemia KW - Comorbidity KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Intracranial Hemorrhages KW - Kidney Diseases KW - Male KW - Middle Aged KW - Netherlands KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND 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.

VL - 45 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24876078?dopt=Abstract ER - TY - JOUR T1 - Association 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. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Nikpoor, Naghmeh A1 - Morrison, Alanna C A1 - Chu, Huan A1 - Ahn, Byung Soo A1 - Wang, Shuai A1 - Dauriz, Marco A1 - Barzilay, Joshua I A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Coresh, Josef A1 - Gibbs, Richard A A1 - Kao, W H Linda A1 - Liu, Ching-Ti A1 - McKnight, Barbara A1 - Muzny, Donna A1 - Pankow, James S A1 - Reid, Jeffrey G A1 - White, Charles C A1 - Johnson, Andrew D A1 - Wong, Tien Y A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Sladek, Robert A1 - Meigs, James B KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - Chromosomes, Human, Pair 11 KW - Cohort Studies KW - Death Domain Receptor Signaling Adaptor Proteins KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Guanine Nucleotide Exchange Factors KW - Heart Diseases KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract ER - TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-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.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study. JF - PLoS One Y1 - 2014 A1 - Alonso, Alvaro A1 - Jensen, Paul N A1 - Lopez, Faye L A1 - Chen, Lin Y A1 - Psaty, Bruce M A1 - Folsom, Aaron R A1 - Heckbert, Susan R KW - Age Distribution KW - Atherosclerosis KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Residence Characteristics KW - Risk KW - Sex Distribution KW - Sick Sinus Syndrome AB -

BACKGROUND: 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.

VL - 9 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25285853?dopt=Abstract ER - TY - JOUR T1 - Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. JF - PLoS One Y1 - 2014 A1 - Bis, Joshua C A1 - DeStefano, Anita A1 - Liu, Xiaoming A1 - Brody, Jennifer A A1 - Choi, Seung Hoan A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Shahar, Eyal A1 - Butler, Kenneth R A1 - Gottesman, Rebecca F A1 - Muzny, Donna A1 - Kovar, Christie L A1 - Psaty, Bruce M A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Gupta, Mayetri A1 - Wolf, Philip A A1 - van Duijn, Cornelia A1 - Gibbs, Richard A A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - Boerwinkle, Eric A1 - Seshadri, Sudha A1 - Fornage, Myriam KW - Cell Adhesion Molecules, Neuronal KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genetic Heterogeneity KW - Humans KW - Introns KW - Ischemia KW - Male KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24959832?dopt=Abstract ER - TY - JOUR T1 - B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. JF - Europace Y1 - 2014 A1 - Sinner, Moritz F A1 - Stepas, Katherine A A1 - Moser, Carlee B A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Franco, Oscar H A1 - Yin, Xiaoyan A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Astor, Brad C A1 - Ballantyne, Christie M A1 - Hoogeveen, Ron C A1 - Arai, Andrew E A1 - Soliman, Elsayed Z A1 - Ellinor, Patrick T A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Pencina, Michael J A1 - Benjamin, Emelia J A1 - Alonso, Alvaro KW - Aged KW - Atrial Fibrillation KW - Biomarkers KW - C-Reactive Protein KW - Europe KW - Female KW - Humans KW - Incidence KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - United States AB -

AIMS: 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.

VL - 16 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract ER - TY - JOUR T1 - The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels. JF - PLoS One Y1 - 2014 A1 - van Leeuwen, Elisabeth M A1 - Smouter, Françoise A S A1 - Kam-Thong, Tony A1 - Karbalai, Nazanin A1 - Smith, Albert V A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Sitlani, Colleen M A1 - Li, Guo A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - White, Charles C A1 - Jaiswal, Alok A1 - Oostra, Ben A A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Jarvelin, Marjo-Riitta A1 - Ripatti, Samuli A1 - Isaacs, Aaron A1 - Müller-Myhsok, Bertram A1 - Karssen, Lennart C A1 - van Duijn, Cornelia M KW - Cholesterol, HDL KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Genome-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.

VL - 9 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25329471?dopt=Abstract ER - TY - JOUR T1 - Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study. JF - Circulation Y1 - 2014 A1 - Wu, Jason H Y A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Song, Xiaoling A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Arachidonic Acid KW - Biomarkers KW - Cohort Studies KW - Coronary Disease KW - Fatty Acids, Omega-3 KW - Fatty Acids, Omega-6 KW - Fatty Acids, Unsaturated KW - Female KW - Follow-Up Studies KW - Humans KW - Linoleic Acid KW - Male KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Stroke KW - Survival Rate KW - United States AB -

BACKGROUND: 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.

VL - 130 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25124495?dopt=Abstract ER - TY - JOUR T1 - Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration. JF - Hypertension Y1 - 2014 A1 - Bots, Michiel L A1 - Groenewegen, Karlijn A A1 - Anderson, Todd J A1 - Britton, Annie R A1 - Dekker, Jacqueline M A1 - Engström, Gunnar A1 - Evans, Greg W A1 - de Graaf, Jacqueline A1 - Grobbee, Diederick E A1 - Hedblad, Bo A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Ikeda, Ai A1 - Kavousi, Maryam A1 - Kitagawa, Kazuo A1 - Kitamura, Akihiko A1 - Ikram, M Arfan A1 - Lonn, Eva M A1 - Lorenz, Matthias W A1 - Mathiesen, Ellisiv B A1 - Nijpels, Giel A1 - Okazaki, Shuhei A1 - O'Leary, Daniel H A1 - Polak, Joseph F A1 - Price, Jacqueline F A1 - Robertson, Christine A1 - Rembold, Christopher M A1 - Rosvall, Maria A1 - Rundek, Tatjana A1 - Salonen, Jukka T A1 - Sitzer, Matthias A1 - Stehouwer, Coen D A A1 - Franco, Oscar H A1 - Peters, Sanne A E A1 - den Ruijter, Hester M KW - Adult KW - Aged KW - Antihypertensive Agents KW - Blood Pressure KW - Cardiovascular Diseases KW - Carotid Artery, Common KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Risk Assessment KW - Risk Factors AB -

Carotid 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.

VL - 63 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24614213?dopt=Abstract ER - TY - JOUR T1 - Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest. JF - Heart Rhythm Y1 - 2014 A1 - Lemaitre, Rozenn N A1 - Johnson, Catherine O A1 - Hesselson, Stephanie A1 - Sotoodehnia, Nona A1 - Sotoodhenia, Nona A1 - McKnight, Barbara A1 - Sitlani, Colleen M A1 - Rea, Thomas D A1 - King, Irena B A1 - Kwok, Pui-Yan A1 - Mak, Angel A1 - Li, Guo A1 - Brody, Jennifer A1 - Larson, Eric A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Huertas-Vazquez, Adriana A1 - Tardif, Jean-Claude A1 - Albert, Christine M A1 - Lyytikäinen, Leo-Pekka A1 - Arking, Dan E A1 - Kääb, Stefan A1 - Huikuri, Heikki V A1 - Krijthe, Bouwe P A1 - Eijgelsheim, Mark A1 - Wang, Ying A A1 - Reinier, Kyndaron A1 - Lehtimäki, Terho A1 - Pulit, Sara L A1 - Brugada, Ramon A1 - Müller-Nurasyid, Martina A1 - Newton-Cheh, Chris H A1 - Karhunen, Pekka J A1 - Stricker, Bruno H A1 - Goyette, Philippe A1 - Rotter, Jerome I A1 - Chugh, Sumeet S A1 - Chakravarti, Aravinda A1 - Jouven, Xavier A1 - Siscovick, David S KW - 1-Acylglycerophosphocholine O-Acyltransferase KW - Aged KW - Algorithms KW - Alleles KW - Case-Control Studies KW - Death, Sudden, Cardiac KW - Fatty Acids KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: 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.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24418166?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a brief dementia screening indicator for primary care. JF - Alzheimers Dement Y1 - 2014 A1 - Barnes, Deborah E A1 - Beiser, Alexa S A1 - Lee, Anne A1 - Langa, Kenneth M A1 - Koyama, Alain A1 - Preis, Sarah R A1 - Neuhaus, John A1 - McCammon, Ryan J A1 - Yaffe, Kristine A1 - Seshadri, Sudha A1 - Haan, Mary N A1 - Weir, David R KW - Aged KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Male KW - Mass Screening KW - Predictive Value of Tests KW - Primary Health Care KW - Proportional Hazards Models KW - Risk Assessment AB -

BACKGROUND: 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.

VL - 10 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24491321?dopt=Abstract ER - TY - JOUR T1 - Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events. JF - Eur J Prev Cardiol Y1 - 2014 A1 - Fowkes, F G R A1 - Murray, G D A1 - Butcher, I A1 - Folsom, A R A1 - Hirsch, A T A1 - Couper, D J A1 - deBacker, G A1 - Kornitzer, M A1 - Newman, A B A1 - Sutton-Tyrrell, K C A1 - Cushman, M A1 - Lee, A J A1 - Price, J F A1 - D'Agostino, R B A1 - Murabito, J M A1 - Norman, Pe A1 - Masaki, K H A1 - Bouter, L M A1 - Heine, R J A1 - Stehouwer, C D A A1 - McDermott, M M A1 - Stoffers, H E J H A1 - Knottnerus, J A A1 - Ogren, M A1 - Hedblad, B A1 - Koenig, W A1 - Meisinger, C A1 - Cauley, J A A1 - Franco, Oh A1 - Hunink, M G M A1 - Hofman, A A1 - Witteman, J C A1 - Criqui, M H A1 - Langer, R D A1 - Hiatt, W R A1 - Hamman, R F KW - Adult KW - Aged KW - Aged, 80 and over KW - Ankle Brachial Index KW - Cardiovascular Diseases KW - Europe KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Models, Statistical KW - Predictive Value of Tests KW - Prognosis KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Time Factors KW - United States KW - Young Adult AB -

BACKGROUND: 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.

VL - 21 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24367001?dopt=Abstract ER - TY - JOUR T1 - Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. JF - Pharmacogenomics J Y1 - 2014 A1 - Avery, C L A1 - Sitlani, C M A1 - Arking, D E A1 - Arnett, D K A1 - Bis, J C A1 - Boerwinkle, E A1 - Buckley, B M A1 - Ida Chen, Y-D A1 - de Craen, A J M A1 - Eijgelsheim, M A1 - Enquobahrie, D A1 - Evans, D S A1 - Ford, I A1 - Garcia, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heckbert, S R A1 - Hochner, H A1 - Hofman, A A1 - Hsueh, W-C A1 - Isaacs, A A1 - Jukema, J W A1 - Knekt, P A1 - Kors, J A A1 - Krijthe, B P A1 - Kristiansson, K A1 - Laaksonen, M A1 - Liu, Y A1 - Li, X A1 - Macfarlane, P W A1 - Newton-Cheh, C A1 - Nieminen, M S A1 - Oostra, B A A1 - Peloso, G M A1 - Porthan, K A1 - Rice, K A1 - Rivadeneira, F F A1 - Rotter, J I A1 - Salomaa, V A1 - Sattar, N A1 - Siscovick, D S A1 - Slagboom, P E A1 - Smith, A V A1 - Sotoodehnia, N A1 - Stott, D J A1 - Stricker, B H A1 - Stürmer, T A1 - Trompet, S A1 - Uitterlinden, A G A1 - van Duijn, C A1 - Westendorp, R G J A1 - Witteman, J C A1 - Whitsel, E A A1 - Psaty, B M KW - Computer Simulation KW - Cross-Sectional Studies KW - Drug-Related Side Effects and Adverse Reactions KW - Electrocardiography KW - European Continental Ancestry Group KW - Gene-Environment Interaction KW - Genome-Wide Association Study KW - Humans KW - Linear Models KW - Long QT Syndrome KW - Markov Chains KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable AB -

Variability 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.

VL - 14 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23459443?dopt=Abstract ER - TY - JOUR T1 - Effect of genetic variants associated with plasma homocysteine levels on stroke risk. JF - Stroke Y1 - 2014 A1 - Cotlarciuc, Ioana A1 - Malik, Rainer A1 - Holliday, Elizabeth G A1 - Ahmadi, Kourosh R A1 - Paré, Guillaume A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Hasan, Nazeeha A1 - Rinne, Paul E A1 - Ikram, M Arfan A1 - Markus, Hugh S A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Kittner, Steven J A1 - Meschia, James F A1 - van Meurs, Joyce B J A1 - Uitterlinden, André G A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Sharma, Pankaj KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome KW - Homocysteine KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk KW - Stroke AB -

BACKGROUND 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.

VL - 45 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24846872?dopt=Abstract ER - TY - JOUR T1 - Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. JF - Am J Hum Genet Y1 - 2014 A1 - Ganesh, Santhi K A1 - Chasman, Daniel I A1 - Larson, Martin G A1 - Guo, Xiuqing A1 - Verwoert, Germain A1 - Bis, Joshua C A1 - Gu, Xiangjun A1 - Smith, Albert V A1 - Yang, Min-Lee A1 - Zhang, Yan A1 - Ehret, Georg A1 - Rose, Lynda M A1 - Hwang, Shih-Jen A1 - Papanicolau, George J A1 - Sijbrands, Eric J A1 - Rice, Kenneth A1 - Eiriksdottir, Gudny A1 - Pihur, Vasyl A1 - Ridker, Paul M A1 - Vasan, Ramachandran S A1 - Newton-Cheh, Christopher A1 - Raffel, Leslie J A1 - Amin, Najaf A1 - Rotter, Jerome I A1 - Liu, Kiang A1 - Launer, Lenore J A1 - Xu, Ming A1 - Caulfield, Mark A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - Vaidya, Dhananjay A1 - Dehghan, Abbas A1 - Li, Guo A1 - Bouchard, Claude A1 - Harris, Tamara B A1 - Zhang, He A1 - Boerwinkle, Eric A1 - Siscovick, David S A1 - Gao, Wei A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Willer, Cristen J A1 - Franco, Oscar H A1 - Huo, Yong A1 - Witteman, Jacqueline C M A1 - Munroe, Patricia B A1 - Gudnason, Vilmundur A1 - Palmas, Walter A1 - van Duijn, Cornelia A1 - Fornage, Myriam A1 - Levy, Daniel A1 - Psaty, Bruce M A1 - Chakravarti, Aravinda KW - Blood Pressure KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Blood 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.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract ER - TY - JOUR T1 - Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. JF - Epidemiology Y1 - 2014 A1 - Seyerle, Amanda A A1 - Young, Alicia M A1 - Jeff, Janina M A1 - Melton, Phillip E A1 - Jorgensen, Neal W A1 - Lin, Yi A1 - Carty, Cara L A1 - Deelman, Ewa A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Jackson, Rebecca D A1 - Martin, Lisa W A1 - Okin, Peter M A1 - Perez, Marco V A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Whitsel, Eric A A1 - North, Kari E A1 - Laston, Sandra A1 - Kooperberg, Charles A1 - Avery, Christy L KW - Aged KW - Continental Population Groups KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

BACKGROUND: 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.

VL - 25 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract ER - TY - JOUR T1 - Extreme deep white matter hyperintensity volumes are associated with African American race. JF - Cerebrovasc Dis Y1 - 2014 A1 - Nyquist, Paul A A1 - Bilgel, Murat S A1 - Gottesman, Rebecca A1 - Yanek, Lisa R A1 - Moy, Taryn F A1 - Becker, Lewis C A1 - Cuzzocreo, Jennifer A1 - Prince, Jerry A1 - Yousem, David M A1 - Becker, Diane M A1 - Kral, Brian G A1 - Vaidya, Dhananjay KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Cerebrovascular Disorders KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Prevalence KW - Risk Factors KW - White Matter AB -

BACKGROUND: 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.

VL - 37 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24686322?dopt=Abstract ER - TY - JOUR T1 - Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). JF - Circulation Y1 - 2014 A1 - Mathew, Jehu S A1 - Sachs, Michael C A1 - Katz, Ronit A1 - Patton, Kristen K A1 - Heckbert, Susan R A1 - Hoofnagle, Andrew N A1 - Alonso, Alvaro A1 - Chonchol, Michel A1 - Deo, Rajat A1 - Ix, Joachim H A1 - Siscovick, David S A1 - Kestenbaum, Bryan A1 - de Boer, Ian H KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Comorbidity KW - Ethnic Groups KW - Female KW - Fibroblast Growth Factor 3 KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Middle Aged KW - Phosphates KW - Proportional Hazards Models KW - Renal Insufficiency, Chronic KW - Risk Factors KW - United States KW - Ventricular Dysfunction, Left KW - Ventricular Remodeling KW - Vitamin D AB -

BACKGROUND: 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.

VL - 130 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24920722?dopt=Abstract ER - TY - JOUR T1 - FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. JF - Hum Mol Genet Y1 - 2014 A1 - Qi, Qibin A1 - Kilpeläinen, Tuomas O A1 - Downer, Mary K A1 - Tanaka, Toshiko A1 - Smith, Caren E A1 - Sluijs, Ivonne A1 - Sonestedt, Emily A1 - Chu, Audrey Y A1 - Renstrom, Frida A1 - Lin, Xiaochen A1 - Ängquist, Lars H A1 - Huang, Jinyan A1 - Liu, Zhonghua A1 - Li, Yanping A1 - Asif Ali, Muhammad A1 - Xu, Min A1 - Ahluwalia, Tarunveer Singh A1 - Boer, Jolanda M A A1 - Chen, Peng A1 - Daimon, Makoto A1 - Eriksson, Johan A1 - Perola, Markus A1 - Friedlander, Yechiel A1 - Gao, Yu-Tang A1 - Heppe, Denise H M A1 - Holloway, John W A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Kim, Yu-Mi A1 - Laaksonen, Maarit A A1 - Jääskeläinen, Tiina A1 - Lee, Nanette R A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Lu, Wei A1 - Luben, Robert N A1 - Manichaikul, Ani A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Monda, Keri L A1 - Ngwa, Julius S A1 - Perusse, Louis A1 - van Rooij, Frank J A A1 - Xiang, Yong-Bing A1 - Wen, Wanqing A1 - Wojczynski, Mary K A1 - Zhu, Jingwen A1 - Borecki, Ingrid B A1 - Bouchard, Claude A1 - Cai, Qiuyin A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Hansen, Torben A1 - Christiansen, Lene A1 - Hofman, Albert A1 - Johansson, Ingegerd A1 - Jørgensen, Torben A1 - Karasawa, Shigeru A1 - Khaw, Kay-Tee A1 - Kim, Mi-Kyung A1 - Kristiansson, Kati A1 - Li, Huaixing A1 - Lin, Xu A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Mikkilä, Vera A1 - Mozaffarian, Dariush A1 - North, Kari A1 - Pedersen, Oluf A1 - Raitakari, Olli A1 - Rissanen, Harri A1 - Tuomilehto, Jaakko A1 - van der Schouw, Yvonne T A1 - Uitterlinden, André G A1 - Zillikens, M Carola A1 - Franco, Oscar H A1 - Shyong Tai, E A1 - Ou Shu, Xiao A1 - Siscovick, David S A1 - Toft, Ulla A1 - Verschuren, W M Monique A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Zheng, Wei A1 - Ridker, Paul M A1 - Kang, Jae H A1 - Liang, Liming A1 - Jensen, Majken K A1 - Curhan, Gary C A1 - Pasquale, Louis R A1 - Hunter, David J A1 - Mohlke, Karen L A1 - Uusitupa, Matti A1 - Cupples, L Adrienne A1 - Rankinen, Tuomo A1 - Orho-Melander, Marju A1 - Wang, Tao A1 - Chasman, Daniel I A1 - Franks, Paul W A1 - Sørensen, Thorkild I A A1 - Hu, Frank B A1 - Loos, Ruth J F A1 - Nettleton, Jennifer A A1 - Qi, Lu KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins AB -

FTO 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.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25104851?dopt=Abstract ER - TY - JOUR T1 - Gender and telomere length: systematic review and meta-analysis. JF - Exp Gerontol Y1 - 2014 A1 - Gardner, Michael A1 - Bann, David A1 - Wiley, Laura A1 - Cooper, Rachel A1 - Hardy, Rebecca A1 - Nitsch, Dorothea A1 - Martin-Ruiz, Carmen A1 - Shiels, Paul A1 - Sayer, Avan Aihie A1 - Barbieri, Michelangela A1 - Bekaert, Sofie A1 - Bischoff, Claus A1 - Brooks-Wilson, Angela A1 - Chen, Wei A1 - Cooper, Cyrus A1 - Christensen, Kaare A1 - De Meyer, Tim A1 - Deary, Ian A1 - Der, Geoff A1 - Diez Roux, Ana A1 - Fitzpatrick, Annette A1 - Hajat, Anjum A1 - Halaschek-Wiener, Julius A1 - Harris, Sarah A1 - Hunt, Steven C A1 - Jagger, Carol A1 - Jeon, Hyo-Sung A1 - Kaplan, Robert A1 - Kimura, Masayuki A1 - Lansdorp, Peter A1 - Li, Changyong A1 - Maeda, Toyoki A1 - Mangino, Massimo A1 - Nawrot, Tim S A1 - Nilsson, Peter A1 - Nordfjall, Katarina A1 - Paolisso, Giuseppe A1 - Ren, Fu A1 - Riabowol, Karl A1 - Robertson, Tony A1 - Roos, Goran A1 - Staessen, Jan A A1 - Spector, Tim A1 - Tang, Nelson A1 - Unryn, Brad A1 - van der Harst, Pim A1 - Woo, Jean A1 - Xing, Chao A1 - Yadegarfar, Mohammad E A1 - Park, Jae Yong A1 - Young, Neal A1 - Kuh, Diana A1 - von Zglinicki, Thomas A1 - Ben-Shlomo, Yoav KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Female KW - Humans KW - Male KW - Middle Aged KW - Sex Factors KW - Telomere AB -

BACKGROUND: 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.

VL - 51 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24365661?dopt=Abstract ER - TY - JOUR T1 - Gene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes. JF - Int J Mol Epidemiol Genet Y1 - 2014 A1 - Suchy-Dicey, Astrid A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - McKnight, Barbara A1 - Rotter, Jerome I A1 - Chen, Yd Ida A1 - Psaty, Bruce M A1 - Enquobahrie, Daniel A AB - Thiazide 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. VL - 5 IS - 1 ER - TY - JOUR T1 - Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. JF - Am J Hum Genet Y1 - 2014 A1 - Simino, Jeannette A1 - Shi, Gang A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - Ehret, Georg B A1 - Gu, Xiangjun A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Sijbrands, Eric A1 - Smith, Albert V A1 - Verwoert, Germaine C A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - Chen, Peng A1 - Cheng, Ching-Yu A1 - Corre, Tanguy A1 - de Boer, Rudolf A A1 - Goel, Anuj A1 - Johnson, Toby A1 - Khor, Chiea-Chuen A1 - Lluís-Ganella, Carla A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Sim, Xueling A1 - Sõber, Siim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Bouchard, Claude A1 - Dehghan, Abbas A1 - Eiriksdottir, Gudny A1 - Elosua, Roberto A1 - Franco, Oscar H A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hercberg, Serge A1 - Hofman, Albert A1 - James, Alan L A1 - Johnson, Andrew D A1 - Kähönen, Mika A1 - Khaw, Kay-Tee A1 - Kutalik, Zoltán A1 - Larson, Martin G A1 - Launer, Lenore J A1 - Li, Guo A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Navis, Gerjan A1 - Ong, Rick Twee-Hee A1 - Papanicolau, George J A1 - Penninx, Brenda W A1 - Psaty, Bruce M A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scott, Robert A A1 - Siscovick, David S A1 - Stolk, Ronald P A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Klauw, Melanie M A1 - Vasan, Ramachandran S A1 - Vithana, Eranga Nishanthie A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Young, Terri L A1 - Aung, Tin A1 - Bochud, Murielle A1 - Farrall, Martin A1 - Hartman, Catharina A A1 - Laan, Maris A1 - Lakatta, Edward G A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Lucas, Gavin A1 - Meneton, Pierre A1 - Palmer, Lyle J A1 - Rettig, Rainer A1 - Snieder, Harold A1 - Tai, E Shyong A1 - Teo, Yik-Ying A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Wong, Tien Yin A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Levy, Daniel A1 - Palmas, Walter A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - van Duijn, Cornelia M A1 - Witteman, Jacqueline C M A1 - Chakravarti, Aravinda A1 - Rao, Dabeeru C KW - Adolescent KW - Adult KW - Age Factors KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Humans KW - Middle Aged KW - Young Adult AB -

Although 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.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24954895?dopt=Abstract ER - TY - JOUR T1 - Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. JF - Hum Mol Genet Y1 - 2014 A1 - Yoneyama, Sachiko A1 - Guo, Yiran A1 - Lanktree, Matthew B A1 - Barnes, Michael R A1 - Elbers, Clara C A1 - Karczewski, Konrad J A1 - Padmanabhan, Sandosh A1 - Bauer, Florianne A1 - Baumert, Jens A1 - Beitelshees, Amber A1 - Berenson, Gerald S A1 - Boer, Jolanda M A A1 - Burke, Gregory A1 - Cade, Brian A1 - Chen, Wei A1 - Cooper-Dehoff, Rhonda M A1 - Gaunt, Tom R A1 - Gieger, Christian A1 - Gong, Yan A1 - Gorski, Mathias A1 - Heard-Costa, Nancy A1 - Johnson, Toby A1 - Lamonte, Michael J A1 - McDonough, Caitrin A1 - Monda, Keri L A1 - Onland-Moret, N Charlotte A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Ordovas, Jose A1 - Peter, Inga A1 - Peters, Annette A1 - Shaffer, Jonathan A1 - Shen, Haiqinq A1 - Smith, Erin A1 - Speilotes, Liz A1 - Thomas, Fridtjof A1 - Thorand, Barbara A1 - Monique Verschuren, W M A1 - Anand, Sonia S A1 - Dominiczak, Anna A1 - Davidson, Karina W A1 - Hegele, Robert A A1 - Heid, Iris A1 - Hofker, Marten H A1 - Huggins, Gordon S A1 - Illig, Thomas A1 - Johnson, Julie A A1 - Kirkland, Susan A1 - König, Wolfgang A1 - Langaee, Taimour Y A1 - McCaffery, Jeanne A1 - Melander, Olle A1 - Mitchell, Braxton D A1 - Munroe, Patricia A1 - Murray, Sarah S A1 - Papanicolaou, George A1 - Redline, Susan A1 - Reilly, Muredach A1 - Samani, Nilesh J A1 - Schork, Nicholas J A1 - van der Schouw, Yvonne T A1 - Shimbo, Daichi A1 - Shuldiner, Alan R A1 - Tobin, Martin D A1 - Wijmenga, Cisca A1 - Yusuf, Salim A1 - Hakonarson, Hakon A1 - Lange, Leslie A A1 - Demerath, Ellen W A1 - Fox, Caroline S A1 - North, Kari E A1 - Reiner, Alex P A1 - Keating, Brendan A1 - Taylor, Kira C KW - Adiposity KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Waist Circumference KW - Waist-Hip Ratio KW - Young Adult AB -

Waist 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.

VL - 23 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract ER - TY - JOUR T1 - A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups. JF - Thromb Res Y1 - 2014 A1 - Weng, Lu-Chen A1 - Tang, Weihong A1 - Rich, Stephen S A1 - Smith, Nicholas L A1 - Redline, Susan A1 - O'Donnell, Christopher J A1 - Basu, Saonli A1 - Reiner, Alexander P A1 - Delaney, Joseph A A1 - Tracy, Russell P A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Yang, Qiong A1 - Folsom, Aaron R A1 - Cushman, Mary KW - Adult KW - Aged KW - Cardiovascular Diseases KW - Ethnic Groups KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Association Studies KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

INTRODUCTION: 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.

VL - 134 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24908450?dopt=Abstract ER - TY - JOUR T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. JF - Nat Genet Y1 - 2014 A1 - Arking, Dan E A1 - Pulit, Sara L A1 - Crotti, Lia A1 - van der Harst, Pim A1 - Munroe, Patricia B A1 - Koopmann, Tamara T A1 - Sotoodehnia, Nona A1 - Rossin, Elizabeth J A1 - Morley, Michael A1 - Wang, Xinchen A1 - Johnson, Andrew D A1 - Lundby, Alicia A1 - Gudbjartsson, Daniel F A1 - Noseworthy, Peter A A1 - Eijgelsheim, Mark A1 - Bradford, Yuki A1 - Tarasov, Kirill V A1 - Dörr, Marcus A1 - Müller-Nurasyid, Martina A1 - Lahtinen, Annukka M A1 - Nolte, Ilja M A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Isaacs, Aaron A1 - Newhouse, Stephen J A1 - Evans, Daniel S A1 - Post, Wendy S A1 - Waggott, Daryl A1 - Lyytikäinen, Leo-Pekka A1 - Hicks, Andrew A A1 - Eisele, Lewin A1 - Ellinghaus, David A1 - Hayward, Caroline A1 - Navarro, Pau A1 - Ulivi, Sheila A1 - Tanaka, Toshiko A1 - Tester, David J A1 - Chatel, Stéphanie A1 - Gustafsson, Stefan A1 - Kumari, Meena A1 - Morris, Richard W A1 - Naluai, Åsa T A1 - Padmanabhan, Sandosh A1 - Kluttig, Alexander A1 - Strohmer, Bernhard A1 - Panayiotou, Andrie G A1 - Torres, Maria A1 - Knoflach, Michael A1 - Hubacek, Jaroslav A A1 - Slowikowski, Kamil A1 - Raychaudhuri, Soumya A1 - Kumar, Runjun D A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shuldiner, Alan R A1 - Alonso, Alvaro A1 - Bader, Joel S A1 - Ehret, Georg A1 - Huang, Hailiang A1 - Kao, W H Linda A1 - Strait, James B A1 - Macfarlane, Peter W A1 - Brown, Morris A1 - Caulfield, Mark J A1 - Samani, Nilesh J A1 - Kronenberg, Florian A1 - Willeit, Johann A1 - Smith, J Gustav A1 - Greiser, Karin H A1 - Meyer Zu Schwabedissen, Henriette A1 - Werdan, Karl A1 - Carella, Massimo A1 - Zelante, Leopoldo A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wright, Alan F A1 - Griffin, Maura A1 - Daly, Mark J A1 - Arnar, David O A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Denny, Joshua C A1 - Roden, Dan M A1 - Zuvich, Rebecca L A1 - Emilsson, Valur A1 - Plump, Andrew S A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Yin, Xiaoyan A1 - Bobbo, Marco A1 - D'Adamo, Adamo P A1 - Iorio, Annamaria A1 - Sinagra, Gianfranco A1 - Carracedo, Angel A1 - Cummings, Steven R A1 - Nalls, Michael A A1 - Jula, Antti A1 - Kontula, Kimmo K A1 - Marjamaa, Annukka A1 - Oikarinen, Lasse A1 - Perola, Markus A1 - Porthan, Kimmo A1 - Erbel, Raimund A1 - Hoffmann, Per A1 - Jöckel, Karl-Heinz A1 - Kälsch, Hagen A1 - Nöthen, Markus M A1 - den Hoed, Marcel A1 - Loos, Ruth J F A1 - Thelle, Dag S A1 - Gieger, Christian A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Peters, Annette A1 - Prucha, Hanna A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - de Boer, Rudolf A A1 - Franke, Lude A1 - van der Vleuten, Pieter A A1 - Beckmann, Britt Maria A1 - Martens, Eimo A1 - Bardai, Abdennasser A1 - Hofman, Nynke A1 - Wilde, Arthur A M A1 - Behr, Elijah R A1 - Dalageorgou, Chrysoula A1 - Giudicessi, John R A1 - Medeiros-Domingo, Argelia A1 - Barc, Julien A1 - Kyndt, Florence A1 - Probst, Vincent A1 - Ghidoni, Alice A1 - Insolia, Roberto A1 - Hamilton, Robert M A1 - Scherer, Stephen W A1 - Brandimarto, Jeffrey A1 - Margulies, Kenneth A1 - Moravec, Christine E A1 - del Greco M, Fabiola A1 - Fuchsberger, Christian A1 - O'Connell, Jeffrey R A1 - Lee, Wai K A1 - Watt, Graham C M A1 - Campbell, Harry A1 - Wild, Sarah H A1 - El Mokhtari, Nour E A1 - Frey, Norbert A1 - Asselbergs, Folkert W A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van den Berg, Maarten P A1 - van Veldhuisen, Dirk J A1 - Kellis, Manolis A1 - Krijthe, Bouwe P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Kors, Jan A A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Kedenko, Lyudmyla A1 - Lamina, Claudia A1 - Oostra, Ben A A1 - Abecasis, Goncalo R A1 - Lakatta, Edward G A1 - Mulas, Antonella A1 - Orrù, Marco A1 - Schlessinger, David A1 - Uda, Manuela A1 - Markus, Marcello R P A1 - Völker, Uwe A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Arnlöv, Johan A1 - Lind, Lars A1 - Sundström, Johan A1 - Syvänen, Ann-Christine A1 - Kivimaki, Mika A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Adamkova, Vera A1 - Kiechl, Stefan A1 - Brion, Maria A1 - Nicolaides, Andrew N A1 - Paulweber, Bernhard A1 - Haerting, Johannes A1 - Dominiczak, Anna F A1 - Nyberg, Fredrik A1 - Whincup, Peter H A1 - Hingorani, Aroon D A1 - Schott, Jean-Jacques A1 - Bezzina, Connie R A1 - Ingelsson, Erik A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Wilson, James F A1 - Rudan, Igor A1 - Franke, Andre A1 - Mühleisen, Thomas W A1 - Pramstaller, Peter P A1 - Lehtimäki, Terho J A1 - Paterson, Andrew D A1 - Parsa, Afshin A1 - Liu, Yongmei A1 - van Duijn, Cornelia M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Jamshidi, Yalda A1 - Salomaa, Veikko A1 - Felix, Stephan B A1 - Sanna, Serena A1 - Ritchie, Marylyn D A1 - Stricker, Bruno H A1 - Stefansson, Kari A1 - Boyer, Laurie A A1 - Cappola, Thomas P A1 - Olsen, Jesper V A1 - Lage, Kasper A1 - Schwartz, Peter J A1 - Kääb, Stefan A1 - Chakravarti, Aravinda A1 - Ackerman, Michael J A1 - Pfeufer, Arne A1 - de Bakker, Paul I W A1 - Newton-Cheh, Christopher KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Calcium Signaling KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Ventricles KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Myocardium KW - Polymorphism, Single Nucleotide AB -

The 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.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Smith, Albert Vernon A1 - Lunetta, Kathryn L A1 - Nalls, Mike A1 - Smith, Jennifer A A1 - Tanaka, Toshiko A1 - Davies, Gail A1 - Yu, Lei A1 - Mirza, Saira Saeed A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Li, Hanyue A1 - Karasik, David A1 - Kiel, Douglas P A1 - Garcia, Melissa A1 - Liu, Yongmei A1 - Faul, Jessica D A1 - Kardia, Sharon Lr A1 - Zhao, Wei A1 - Ferrucci, Luigi A1 - Allerhand, Michael A1 - Liewald, David C A1 - Redmond, Paul A1 - Starr, John M A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Direk, Nese A1 - Ikram, Mohammed Arfan A1 - Uitterlinden, Andre A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Grabe, Hans J A1 - Launer, Lenore A1 - Murabito, Joanne M A1 - Singleton, Andrew B A1 - Weir, David R A1 - Bandinelli, Stefania A1 - Deary, Ian J A1 - Bennett, David A A1 - Tiemeier, Henning A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Arking, Dan E KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models AB -

BACKGROUND: 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.

VL - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract ER - TY - JOUR T1 - Genetic variants related to height and risk of atrial fibrillation: the cardiovascular health study. JF - Am J Epidemiol Y1 - 2014 A1 - Rosenberg, Michael A A1 - Kaplan, Robert C A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Newton-Cheh, Christopher A1 - Mukamal, Kenneth J KW - African Americans KW - Aged KW - Atrial Fibrillation KW - Body Height KW - Endonucleases KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Longitudinal Studies KW - Male KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors AB -

Increased 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.

VL - 180 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24944287?dopt=Abstract ER - TY - JOUR T1 - Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. JF - PLoS One Y1 - 2014 A1 - Escott-Price, Valentina A1 - Bellenguez, Céline A1 - Wang, Li-San A1 - Choi, Seung-Hoan A1 - Harold, Denise A1 - Jones, Lesley A1 - Holmans, Peter A1 - Gerrish, Amy A1 - Vedernikov, Alexey A1 - Richards, Alexander A1 - DeStefano, Anita L A1 - Lambert, Jean-Charles A1 - Ibrahim-Verbaas, Carla A A1 - Naj, Adam C A1 - Sims, Rebecca A1 - Jun, Gyungah A1 - Bis, Joshua C A1 - Beecham, Gary W A1 - Grenier-Boley, Benjamin A1 - Russo, Giancarlo A1 - Thornton-Wells, Tricia A A1 - Denning, Nicola A1 - Smith, Albert V A1 - Chouraki, Vincent A1 - Thomas, Charlene A1 - Ikram, M Arfan A1 - Zelenika, Diana A1 - Vardarajan, Badri N A1 - Kamatani, Yoichiro A1 - Lin, Chiao-Feng A1 - Schmidt, Helena A1 - Kunkle, Brian A1 - Dunstan, Melanie L A1 - Vronskaya, Maria A1 - Johnson, Andrew D A1 - Ruiz, Agustin A1 - Bihoreau, Marie-Thérèse A1 - Reitz, Christiane A1 - Pasquier, Florence A1 - Hollingworth, Paul A1 - Hanon, Olivier A1 - Fitzpatrick, Annette L A1 - Buxbaum, Joseph D A1 - Campion, Dominique A1 - Crane, Paul K A1 - Baldwin, Clinton A1 - Becker, Tim A1 - Gudnason, Vilmundur A1 - Cruchaga, Carlos A1 - Craig, David A1 - Amin, Najaf A1 - Berr, Claudine A1 - Lopez, Oscar L A1 - De Jager, Philip L A1 - Deramecourt, Vincent A1 - Johnston, Janet A A1 - Evans, Denis A1 - Lovestone, Simon A1 - Letenneur, Luc A1 - Hernandez, Isabel A1 - Rubinsztein, David C A1 - Eiriksdottir, Gudny A1 - Sleegers, Kristel A1 - Goate, Alison M A1 - Fiévet, Nathalie A1 - Huentelman, Matthew J A1 - Gill, Michael A1 - Brown, Kristelle A1 - Kamboh, M Ilyas A1 - Keller, Lina A1 - Barberger-Gateau, Pascale A1 - McGuinness, Bernadette A1 - Larson, Eric B A1 - Myers, Amanda J A1 - Dufouil, Carole A1 - Todd, Stephen A1 - Wallon, David A1 - Love, Seth A1 - Rogaeva, Ekaterina A1 - Gallacher, John A1 - George-Hyslop, Peter St A1 - Clarimon, Jordi A1 - Lleo, Alberto A1 - Bayer, Anthony A1 - Tsuang, Debby W A1 - Yu, Lei A1 - Tsolaki, Magda A1 - Bossù, Paola A1 - Spalletta, Gianfranco A1 - Proitsi, Petra A1 - Collinge, John A1 - Sorbi, Sandro A1 - Garcia, Florentino Sanchez A1 - Fox, Nick C A1 - Hardy, John A1 - Naranjo, Maria Candida Deniz A1 - Bosco, Paolo A1 - Clarke, Robert A1 - Brayne, Carol A1 - Galimberti, Daniela A1 - Scarpini, Elio A1 - Bonuccelli, Ubaldo A1 - Mancuso, Michelangelo A1 - Siciliano, Gabriele A1 - Moebus, Susanne A1 - Mecocci, Patrizia A1 - Zompo, Maria Del A1 - Maier, Wolfgang A1 - Hampel, Harald A1 - Pilotto, Alberto A1 - Frank-García, Ana A1 - Panza, Francesco A1 - Solfrizzi, Vincenzo A1 - Caffarra, Paolo A1 - Nacmias, Benedetta A1 - Perry, William A1 - Mayhaus, Manuel A1 - Lannfelt, Lars A1 - Hakonarson, Hakon A1 - Pichler, Sabrina A1 - Carrasquillo, Minerva M A1 - Ingelsson, Martin A1 - Beekly, Duane A1 - Alvarez, Victoria A1 - Zou, Fanggeng A1 - Valladares, Otto A1 - Younkin, Steven G A1 - Coto, Eliecer A1 - Hamilton-Nelson, Kara L A1 - Gu, Wei A1 - Razquin, Cristina A1 - Pastor, Pau A1 - Mateo, Ignacio A1 - Owen, Michael J A1 - Faber, Kelley M A1 - Jonsson, Palmi V A1 - Combarros, Onofre A1 - O'Donovan, Michael C A1 - Cantwell, Laura B A1 - Soininen, Hilkka A1 - Blacker, Deborah A1 - Mead, Simon A1 - Mosley, Thomas H A1 - Bennett, David A A1 - Harris, Tamara B A1 - Fratiglioni, Laura A1 - Holmes, Clive A1 - de Bruijn, Renee F A G A1 - Passmore, Peter A1 - Montine, Thomas J A1 - Bettens, Karolien A1 - Rotter, Jerome I A1 - Brice, Alexis A1 - Morgan, Kevin A1 - Foroud, Tatiana M A1 - Kukull, Walter A A1 - Hannequin, Didier A1 - Powell, John F A1 - Nalls, Michael A A1 - Ritchie, Karen A1 - Lunetta, Kathryn L A1 - Kauwe, John S K A1 - Boerwinkle, Eric A1 - Riemenschneider, Matthias A1 - Boada, Merce A1 - Hiltunen, Mikko A1 - Martin, Eden R A1 - Schmidt, Reinhold A1 - Rujescu, Dan A1 - Dartigues, Jean-François A1 - Mayeux, Richard A1 - Tzourio, Christophe A1 - Hofman, Albert A1 - Nöthen, Markus M A1 - Graff, Caroline A1 - Psaty, Bruce M A1 - Haines, Jonathan L A1 - Lathrop, Mark A1 - Pericak-Vance, Margaret A A1 - Launer, Lenore J A1 - Van Broeckhoven, Christine A1 - Farrer, Lindsay A A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Seshadri, Sudha A1 - Schellenberg, Gerard D A1 - Amouyel, Philippe A1 - Williams, Julie KW - Alzheimer Disease KW - Carrier Proteins KW - Case-Control Studies KW - Genome-Wide Association Study KW - Heat-Shock Proteins KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptors, Antigen, B-Cell AB -

BACKGROUND: 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.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

Forced 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.

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. JF - Arterioscler Thromb Vasc Biol Y1 - 2014 A1 - Huang, Jie A1 - Huffman, Jennifer E A1 - Yamakuchi, Munekazu A1 - Yamkauchi, Munekazu A1 - Trompet, Stella A1 - Asselbergs, Folkert W A1 - Sabater-Lleal, Maria A1 - Trégouët, David-Alexandre A1 - Chen, Wei-Min A1 - Smith, Nicholas L A1 - Kleber, Marcus E A1 - Shin, So-Youn A1 - Becker, Diane M A1 - Tang, Weihong A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Truong, Vinh A1 - Folkersen, Lasse A1 - Yang, Qiong A1 - Oudot-Mellkah, Tiphaine A1 - Buckley, Brendan M A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Campbell, Harry A1 - Silbernagel, Günther A1 - Vitart, Veronique A1 - Rudan, Igor A1 - Tofler, Geoffrey H A1 - Navis, Gerjan J A1 - DeStefano, Anita A1 - Wright, Alan F A1 - Chen, Ming-Huei A1 - de Craen, Anton J M A1 - Worrall, Bradford B A1 - Rudnicka, Alicja R A1 - Rumley, Ann A1 - Bookman, Ebony B A1 - Psaty, Bruce M A1 - Chen, Fang A1 - Keene, Keith L A1 - Franco, Oscar H A1 - Böhm, Bernhard O A1 - Uitterlinden, André G A1 - Carter, Angela M A1 - Jukema, J Wouter A1 - Sattar, Naveed A1 - Bis, Joshua C A1 - Ikram, Mohammad A A1 - Sale, Michèle M A1 - McKnight, Barbara A1 - Fornage, Myriam A1 - Ford, Ian A1 - Taylor, Kent A1 - Slagboom, P Eline A1 - McArdle, Wendy L A1 - Hsu, Fang-Chi A1 - Franco-Cereceda, Anders A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Furie, Karen L A1 - Cushman, Mary A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Wilson, James F A1 - Westendorp, Rudi G J A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Tracy, Russell P A1 - Polasek, Ozren A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Cambien, Francois A1 - Stott, David J A1 - Lowe, Gordon D A1 - Spector, Timothy D A1 - Meigs, James B A1 - März, Winfried A1 - Eriksson, Per A1 - Becker, Lewis C A1 - Morange, Pierre-Emmanuel A1 - Soranzo, Nicole A1 - Williams, Scott M A1 - Hayward, Caroline A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Lowenstein, Charles J A1 - Strachan, David P A1 - O'Donnell, Christopher J KW - Aged KW - Cells, Cultured KW - Coronary Artery Disease KW - Endothelial Cells KW - Europe KW - Female KW - Gene Expression Regulation KW - Gene Silencing KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - R-SNARE Proteins KW - Risk Factors KW - Stroke KW - Syntaxin 1 KW - Tissue Plasminogen Activator KW - Transfection KW - United States KW - Up-Regulation AB -

OBJECTIVE: 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.

VL - 34 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Lüneburg, Nicole A1 - Lieb, Wolfgang A1 - Zeller, Tanja A1 - Chen, Ming-Huei A1 - Maas, Renke A1 - Carter, Angela M A1 - Xanthakis, Vanessa A1 - Glazer, Nicole L A1 - Schwedhelm, Edzard A1 - Seshadri, Sudha A1 - Ikram, Mohammad Arfan A1 - Longstreth, William T A1 - Fornage, Myriam A1 - König, Inke R A1 - Loley, Christina A1 - Ojeda, Francisco M A1 - Schillert, Arne A1 - Wang, Thomas J A1 - Sticht, Heinrich A1 - Kittel, Anja A1 - König, Jörg A1 - Benjamin, Emelia J A1 - Sullivan, Lisa M A1 - Bernges, Isabel A1 - Anderssohn, Maike A1 - Ziegler, Andreas A1 - Gieger, Christian A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Wild, Philipp S A1 - Schunkert, Heribert A1 - Psaty, Bruce M A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Smith, Nicholas A1 - Lackner, Karl A1 - Lunetta, Kathryn L A1 - Blankenberg, Stefan A1 - Erdmann, Jeanette A1 - Münzel, Thomas A1 - Grant, Peter J A1 - Vasan, Ramachandran S A1 - Böger, Rainer H KW - Adult KW - Aged KW - Amidohydrolases KW - Arginine KW - Binding Sites KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - HEK293 Cells KW - Humans KW - Male KW - Mediator Complex KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Structure, Tertiary KW - Risk Factors KW - Stroke KW - Substrate Specificity KW - Transaminases AB -

BACKGROUND: 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.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Guan, Weihua A1 - Steffen, Brian T A1 - Lemaitre, Rozenn N A1 - Wu, Jason H Y A1 - Tanaka, Toshiko A1 - Manichaikul, Ani A1 - Foy, Millennia A1 - Rich, Stephen S A1 - Wang, Lu A1 - Nettleton, Jennifer A A1 - Tang, Weihong A1 - Gu, Xiangjun A1 - Bandinelli, Stafania A1 - King, Irena B A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Djoussé, Luc A1 - Chen, Yii-Der Ida A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Mozafarrian, Dariush A1 - Tsai, Michael Y A1 - Steffen, Lyn M KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Chromosomes, Human, Pair 10 KW - Chromosomes, Human, Pair 16 KW - Chromosomes, Human, Pair 6 KW - Fatty Acid Desaturases KW - Fatty Acids, Omega-6 KW - Female KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24823311?dopt=Abstract ER - TY - JOUR T1 - Glycated hemoglobin measurement and prediction of cardiovascular disease. JF - JAMA Y1 - 2014 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Khan, Hassan A1 - Butterworth, Adam S A1 - Wormser, David A1 - Kaptoge, Stephen A1 - Kondapally Seshasai, Sreenivasa Rao A1 - Thompson, Alex A1 - Sarwar, Nadeem A1 - Willeit, Peter A1 - Ridker, Paul M A1 - Barr, Elizabeth L M A1 - Khaw, Kay-Tee A1 - Psaty, Bruce M A1 - Brenner, Hermann A1 - Balkau, Beverley A1 - Dekker, Jacqueline M A1 - Lawlor, Debbie A A1 - Daimon, Makoto A1 - Willeit, Johann A1 - Njølstad, Inger A1 - Nissinen, Aulikki A1 - Brunner, Eric J A1 - Kuller, Lewis H A1 - Price, Jackie F A1 - Sundström, Johan A1 - Knuiman, Matthew W A1 - Feskens, Edith J M A1 - Verschuren, W M M A1 - Wald, Nicholas A1 - Bakker, Stephan J L A1 - Whincup, Peter H A1 - Ford, Ian A1 - Goldbourt, Uri A1 - Gómez-de-la-Cámara, Agustín A1 - Gallacher, John A1 - Simons, Leon A A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Björkelund, Cecilia A1 - Blazer, Dan G A1 - Wassertheil-Smoller, Sylvia A1 - Onat, Altan A1 - Marín Ibañez, Alejandro A1 - Casiglia, Edoardo A1 - Jukema, J Wouter A1 - Simpson, Lara M A1 - Giampaoli, Simona A1 - Nordestgaard, Børge G A1 - Selmer, Randi A1 - Wennberg, Patrik A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Dankner, Rachel A1 - Barrett-Connor, Elizabeth A1 - Kavousi, Maryam A1 - Gudnason, Vilmundur A1 - Evans, Denis A1 - Wallace, Robert B A1 - Cushman, Mary A1 - D'Agostino, Ralph B A1 - Umans, Jason G A1 - Kiyohara, Yutaka A1 - Nakagawa, Hidaeki A1 - Sato, Shinichi A1 - Gillum, Richard F A1 - Folsom, Aaron R A1 - van der Schouw, Yvonne T A1 - Moons, Karel G A1 - Griffin, Simon J A1 - Sattar, Naveed A1 - Wareham, Nicholas J A1 - Selvin, Elizabeth A1 - Thompson, Simon G A1 - Danesh, John KW - Aged KW - C-Reactive Protein KW - Cholesterol, HDL KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Glycated Hemoglobin A KW - Humans KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Assessment KW - Stroke AB -

IMPORTANCE: 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.

VL - 311 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24668104?dopt=Abstract ER - TY - JOUR T1 - Heritability of and mortality prediction with a longevity phenotype: the healthy aging index. JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Sanders, Jason L A1 - Minster, Ryan L A1 - Barmada, M Michael A1 - Matteini, Amy M A1 - Boudreau, Robert M A1 - Christensen, Kaare A1 - Mayeux, Richard A1 - Borecki, Ingrid B A1 - Zhang, Qunyuan A1 - Perls, Thomas A1 - Newman, Anne B KW - Aged KW - Aging KW - Cardiovascular Diseases KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Health Behavior KW - Humans KW - Longevity KW - Male KW - Phenotype KW - Retrospective Studies KW - Risk Factors KW - Survival Rate KW - United States AB -

BACKGROUND: 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.

VL - 69 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23913930?dopt=Abstract ER - TY - JOUR T1 - Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. JF - PLoS Genet Y1 - 2014 A1 - Medici, Marco A1 - Porcu, Eleonora A1 - Pistis, Giorgio A1 - Teumer, Alexander A1 - Brown, Suzanne J A1 - Jensen, Richard A A1 - Rawal, Rajesh A1 - Roef, Greet L A1 - Plantinga, Theo S A1 - Vermeulen, Sita H A1 - Lahti, Jari A1 - Simmonds, Matthew J A1 - Husemoen, Lise Lotte N A1 - Freathy, Rachel M A1 - Shields, Beverley M A1 - Pietzner, Diana A1 - Nagy, Rebecca A1 - Broer, Linda A1 - Chaker, Layal A1 - Korevaar, Tim I M A1 - Plia, Maria Grazia A1 - Sala, Cinzia A1 - Völker, Uwe A1 - Richards, J Brent A1 - Sweep, Fred C A1 - Gieger, Christian A1 - Corre, Tanguy A1 - Kajantie, Eero A1 - Thuesen, Betina A1 - Taes, Youri E A1 - Visser, W Edward A1 - Hattersley, Andrew T A1 - Kratzsch, Jürgen A1 - Hamilton, Alexander A1 - Li, Wei A1 - Homuth, Georg A1 - Lobina, Monia A1 - Mariotti, Stefano A1 - Soranzo, Nicole A1 - Cocca, Massimiliano A1 - Nauck, Matthias A1 - Spielhagen, Christin A1 - Ross, Alec A1 - Arnold, Alice A1 - van de Bunt, Martijn A1 - Liyanarachchi, Sandya A1 - Heier, Margit A1 - Grabe, Hans Jörgen A1 - Masciullo, Corrado A1 - Galesloot, Tessel E A1 - Lim, Ee M A1 - Reischl, Eva A1 - Leedman, Peter J A1 - Lai, Sandra A1 - Delitala, Alessandro A1 - Bremner, Alexandra P A1 - Philips, David I W A1 - Beilby, John P A1 - Mulas, Antonella A1 - Vocale, Matteo A1 - Abecasis, Goncalo A1 - Forsen, Tom A1 - James, Alan A1 - Widen, Elisabeth A1 - Hui, Jennie A1 - Prokisch, Holger A1 - Rietzschel, Ernst E A1 - Palotie, Aarno A1 - Feddema, Peter A1 - Fletcher, Stephen J A1 - Schramm, Katharina A1 - Rotter, Jerome I A1 - Kluttig, Alexander A1 - Radke, Dörte A1 - Traglia, Michela A1 - Surdulescu, Gabriela L A1 - He, Huiling A1 - Franklyn, Jayne A A1 - Tiller, Daniel A1 - Vaidya, Bijay A1 - De Meyer, Tim A1 - Jørgensen, Torben A1 - Eriksson, Johan G A1 - O'Leary, Peter C A1 - Wichmann, Eric A1 - Hermus, Ad R A1 - Psaty, Bruce M A1 - Ittermann, Till A1 - Hofman, Albert A1 - Bosi, Emanuele A1 - Schlessinger, David A1 - Wallaschofski, Henri A1 - Pirastu, Nicola A1 - Aulchenko, Yurii S A1 - de la Chapelle, Albert A1 - Netea-Maier, Romana T A1 - Gough, Stephen C L A1 - Meyer Zu Schwabedissen, Henriette A1 - Frayling, Timothy M A1 - Kaufman, Jean-Marc A1 - Linneberg, Allan A1 - Räikkönen, Katri A1 - Smit, Johannes W A A1 - Kiemeney, Lambertus A A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Walsh, John P A1 - Meisinger, Christa A1 - den Heijer, Martin A1 - Visser, Theo J A1 - Spector, Timothy D A1 - Wilson, Scott G A1 - Völzke, Henry A1 - Cappola, Anne A1 - Toniolo, Daniela A1 - Sanna, Serena A1 - Naitza, Silvia A1 - Peeters, Robin P KW - Autoantibodies KW - Genetic Loci KW - Genome-Wide Association Study KW - Graves Disease KW - Hashimoto Disease KW - Humans KW - Iodide Peroxidase KW - Risk Factors KW - Thyroiditis, Autoimmune KW - Thyrotropin AB -

Autoimmune 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.

VL - 10 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24586183?dopt=Abstract ER - TY - JOUR T1 - Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. JF - Circulation Y1 - 2014 A1 - Sinner, Moritz F A1 - Tucker, Nathan R A1 - Lunetta, Kathryn L A1 - Ozaki, Kouichi A1 - Smith, J Gustav A1 - Trompet, Stella A1 - Bis, Joshua C A1 - Lin, Honghuang A1 - Chung, Mina K A1 - Nielsen, Jonas B A1 - Lubitz, Steven A A1 - Krijthe, Bouwe P A1 - Magnani, Jared W A1 - Ye, Jiangchuan A1 - Gollob, Michael H A1 - Tsunoda, Tatsuhiko A1 - Müller-Nurasyid, Martina A1 - Lichtner, Peter A1 - Peters, Annette A1 - Dolmatova, Elena A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Psaty, Bruce M A1 - Smith, Nicholas L A1 - Jukema, J Wouter A1 - Chasman, Daniel I A1 - Albert, Christine M A1 - Ebana, Yusuke A1 - Furukawa, Tetsushi A1 - Macfarlane, Peter W A1 - Harris, Tamara B A1 - Darbar, Dawood A1 - Dörr, Marcus A1 - Holst, Anders G A1 - Svendsen, Jesper H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Gudnason, Vilmundur A1 - Isobe, Mitsuaki A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Rosand, Jonathan A1 - Van Wagoner, David R A1 - Benjamin, Emelia J A1 - Milan, David J A1 - Melander, Olle A1 - Heckbert, Susan R A1 - Ford, Ian A1 - Liu, Yongmei A1 - Barnard, John A1 - Olesen, Morten S A1 - Stricker, Bruno H C A1 - Tanaka, Toshihiro A1 - Kääb, Stefan A1 - Ellinor, Patrick T KW - Aged KW - Animals KW - Atrial Fibrillation KW - Chromosome Mapping KW - Connexin 43 KW - Europe KW - Female KW - Gene Knockdown Techniques KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Homeodomain Proteins KW - Humans KW - Japan KW - Male KW - Middle Aged KW - Muscle Proteins KW - Nuclear Proteins KW - Quantitative Trait Loci KW - Repressor Proteins KW - T-Box Domain Proteins KW - Transcription Factors KW - Ubiquitin-Protein Ligases KW - Zebrafish KW - Zebrafish Proteins AB -

BACKGROUND: 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.

VL - 130 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25124494?dopt=Abstract ER - TY - JOUR T1 - Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. JF - Hum Genet Y1 - 2014 A1 - Ellis, Jaclyn A1 - Lange, Ethan M A1 - Li, Jin A1 - Dupuis, Josée A1 - Baumert, Jens A1 - Walston, Jeremy D A1 - Keating, Brendan J A1 - Durda, Peter A1 - Fox, Ervin R A1 - Palmer, Cameron D A1 - Meng, Yan A A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Schnabel, Renate B A1 - Marzi, Carola S A1 - Larkin, Emma A1 - Martin, Lisa W A1 - Bis, Joshua C A1 - Auer, Paul A1 - Ramachandran, Vasan S A1 - Gabriel, Stacey B A1 - Willis, Monte S A1 - Pankow, James S A1 - Papanicolaou, George J A1 - Rotter, Jerome I A1 - Ballantyne, Christie M A1 - Gross, Myron D A1 - Lettre, Guillaume A1 - Wilson, James G A1 - Peters, Ulrike A1 - Koenig, Wolfgang A1 - Tracy, Russell P A1 - Redline, Susan A1 - Reiner, Alex P A1 - Benjamin, Emelia J A1 - Lange, Leslie A KW - Adult KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - CD36 Antigens KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

C-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.

VL - 133 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24643644?dopt=Abstract ER - TY - JOUR T1 - Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. JF - PLoS One Y1 - 2014 A1 - Tang, Wenbo A1 - Kowgier, Matthew A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Joubert, Bonnie R A1 - Hodge, Emily A1 - Gharib, Sina A A1 - Smith, Albert V A1 - Ruczinski, Ingo A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Harris, Tamara B A1 - Hansel, Nadia N A1 - Launer, Lenore J A1 - Barnes, Kathleen C A1 - Hansen, Joyanna G A1 - Albrecht, Eva A1 - Aldrich, Melinda C A1 - Allerhand, Michael A1 - Barr, R Graham A1 - Brusselle, Guy G A1 - Couper, David J A1 - Curjuric, Ivan A1 - Davies, Gail A1 - Deary, Ian J A1 - Dupuis, Josée A1 - Fall, Tove A1 - Foy, Millennia A1 - Franceschini, Nora A1 - Gao, Wei A1 - Gläser, Sven A1 - Gu, Xiangjun A1 - Hancock, Dana B A1 - Heinrich, Joachim A1 - Hofman, Albert A1 - Imboden, Medea A1 - Ingelsson, Erik A1 - James, Alan A1 - Karrasch, Stefan A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Kumar, Ashish A1 - Lahousse, Lies A1 - Li, Guo A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Lumley, Thomas A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Musk, Bill A1 - North, Kari E A1 - Palmer, Lyle J A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schulz, Holger A1 - Smith, Lewis J A1 - Sood, Akshay A1 - Starr, John M A1 - Strachan, David P A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Voorman, Arend A1 - Wain, Louise V A1 - Wells, Martin T A1 - Wilk, Jemma B A1 - Williams, O Dale A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - London, Stephanie J A1 - Fornage, Myriam A1 - Tobin, Martin D A1 - O'Connor, George T A1 - Hall, Ian P A1 - Cassano, Patricia A KW - Adult KW - Chromosomes, Human, Pair 11 KW - Female KW - Gene Expression Regulation KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Male KW - Respiration AB -

BACKGROUND: 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.

VL - 9 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract ER - TY - JOUR T1 - Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. JF - Nat Genet Y1 - 2014 A1 - Nalls, Mike A A1 - Pankratz, Nathan A1 - Lill, Christina M A1 - Do, Chuong B A1 - Hernandez, Dena G A1 - Saad, Mohamad A1 - DeStefano, Anita L A1 - Kara, Eleanna A1 - Bras, Jose A1 - Sharma, Manu A1 - Schulte, Claudia A1 - Keller, Margaux F A1 - Arepalli, Sampath A1 - Letson, Christopher A1 - Edsall, Connor A1 - Stefansson, Hreinn A1 - Liu, Xinmin A1 - Pliner, Hannah A1 - Lee, Joseph H A1 - Cheng, Rong A1 - Ikram, M Arfan A1 - Ioannidis, John P A A1 - Hadjigeorgiou, Georgios M A1 - Bis, Joshua C A1 - Martinez, Maria A1 - Perlmutter, Joel S A1 - Goate, Alison A1 - Marder, Karen A1 - Fiske, Brian A1 - Sutherland, Margaret A1 - Xiromerisiou, Georgia A1 - Myers, Richard H A1 - Clark, Lorraine N A1 - Stefansson, Kari A1 - Hardy, John A A1 - Heutink, Peter A1 - Chen, Honglei A1 - Wood, Nicholas W A1 - Houlden, Henry A1 - Payami, Haydeh A1 - Brice, Alexis A1 - Scott, William K A1 - Gasser, Thomas A1 - Bertram, Lars A1 - Eriksson, Nicholas A1 - Foroud, Tatiana A1 - Singleton, Andrew B KW - Case-Control Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Parkinson Disease KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We 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.

VL - 46 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25064009?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in APOC3, triglycerides, and coronary disease. JF - N Engl J Med Y1 - 2014 A1 - Crosby, Jacy A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Crosslin, David R A1 - Stitziel, Nathan O A1 - Lange, Leslie A A1 - Lu, Yingchang A1 - Tang, Zheng-Zheng A1 - Zhang, He A1 - Hindy, George A1 - Masca, Nicholas A1 - Stirrups, Kathleen A1 - Kanoni, Stavroula A1 - Do, Ron A1 - Jun, Goo A1 - Hu, Youna A1 - Kang, Hyun Min A1 - Xue, Chenyi A1 - Goel, Anuj A1 - Farrall, Martin A1 - Duga, Stefano A1 - Merlini, Pier Angelica A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Olivieri, Oliviero A1 - Martinelli, Nicola A1 - Yin, Wu A1 - Reilly, Dermot A1 - Speliotes, Elizabeth A1 - Fox, Caroline S A1 - Hveem, Kristian A1 - Holmen, Oddgeir L A1 - Nikpay, Majid A1 - Farlow, Deborah N A1 - Assimes, Themistocles L A1 - Franceschini, Nora A1 - Robinson, Jennifer A1 - North, Kari E A1 - Martin, Lisa W A1 - DePristo, Mark A1 - Gupta, Namrata A1 - Escher, Stefan A A1 - Jansson, Jan-Håkan A1 - Van Zuydam, Natalie A1 - Palmer, Colin N A A1 - Wareham, Nicholas A1 - Koch, Werner A1 - Meitinger, Thomas A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Erbel, Raimund A1 - König, Inke R A1 - Kruppa, Jochen A1 - Degenhardt, Franziska A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ballantyne, Christie M A1 - Abecasis, Goncalo A1 - Ordovas, Jose M A1 - Melander, Olle A1 - Watkins, Hugh A1 - Orho-Melander, Marju A1 - Ardissino, Diego A1 - Loos, Ruth J F A1 - McPherson, Ruth A1 - Willer, Cristen J A1 - Erdmann, Jeanette A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Deloukas, Panos A1 - Schunkert, Heribert A1 - Wilson, James G A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Lin, Dan-Yu A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Nickerson, Deborah A A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Reiner, Alex P A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar KW - African Continental Ancestry Group KW - Apolipoprotein C-III KW - Coronary Disease KW - European Continental Ancestry Group KW - Exome KW - Genotype KW - Heterozygote KW - Humans KW - Liver KW - Mutation KW - Risk Factors KW - Sequence Analysis, DNA KW - Triglycerides AB -

BACKGROUND: 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.).

VL - 371 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract ER - TY - JOUR T1 - A low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker. JF - J Am Heart Assoc Y1 - 2014 A1 - Waterworth, Dawn M A1 - Li, Li A1 - Scott, Robert A1 - Warren, Liling A1 - Gillson, Christopher A1 - Aponte, Jennifer A1 - Sarov-Blat, Lea A1 - Sprecher, Dennis A1 - Dupuis, Josée A1 - Reiner, Alex A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Lin, Honghuang A1 - McPherson, Ruth A1 - Chissoe, Stephanie A1 - Wareham, Nick A1 - Ehm, Margaret G KW - Adult KW - Aged KW - Cardiovascular Diseases KW - Dyslipidemias KW - Exome KW - Female KW - Genotype KW - Humans KW - Linear Models KW - Logistic Models KW - Male KW - Metabolic Syndrome X KW - Middle Aged KW - Mitogen-Activated Protein Kinase 11 KW - Mitogen-Activated Protein Kinase 14 KW - Obesity KW - Peroxidase KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Risk Factors KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 3 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25164947?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. JF - Neurology Y1 - 2014 A1 - Kilarski, Laura L A1 - Achterberg, Sefanja A1 - Devan, William J A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Lindgren, Arne A1 - Pare, Guillame A1 - Sharma, Pankaj A1 - Slowik, Agniesczka A1 - Thijs, Vincent A1 - Walters, Matthew A1 - Worrall, Bradford B A1 - Sale, Michèle M A1 - Algra, Ale A1 - Kappelle, L Jaap A1 - Wijmenga, Cisca A1 - Norrving, Bo A1 - Sandling, Johanna K A1 - Rönnblom, Lars A1 - Goris, An A1 - Franke, Andre A1 - Sudlow, Cathie A1 - Rothwell, Peter M A1 - Levi, Christopher A1 - Holliday, Elizabeth G A1 - Fornage, Myriam A1 - Psaty, Bruce A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnar A1 - Seshadri, Sudha A1 - Mitchell, Braxton D A1 - Kittner, Steven A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Bis, Joshua C A1 - Boncoraglio, Giorgio B A1 - Meschia, James A1 - Ikram, M Arfan A1 - Hansen, Bjorn M A1 - Montaner, Joan A1 - Thorleifsson, Gudmar A1 - Stefanson, Kari A1 - Rosand, Jonathan A1 - de Bakker, Paul I W A1 - Farrall, Martin A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Bevan, Steve KW - Brain Ischemia KW - Cerebral Hemorrhage KW - Chromosomes, Human, Pair 12 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk KW - Stroke AB -

OBJECTIVES: 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.

VL - 83 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25031287?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. JF - PLoS Genet Y1 - 2014 A1 - Ng, Maggie C Y A1 - Shriner, Daniel A1 - Chen, Brian H A1 - Li, Jiang A1 - Chen, Wei-Min A1 - Guo, Xiuqing A1 - Liu, Jiankang A1 - Bielinski, Suzette J A1 - Yanek, Lisa R A1 - Nalls, Michael A A1 - Comeau, Mary E A1 - Rasmussen-Torvik, Laura J A1 - Jensen, Richard A A1 - Evans, Daniel S A1 - Sun, Yan V A1 - An, Ping A1 - Patel, Sanjay R A1 - Lu, Yingchang A1 - Long, Jirong A1 - Armstrong, Loren L A1 - Wagenknecht, Lynne A1 - Yang, Lingyao A1 - Snively, Beverly M A1 - Palmer, Nicholette D A1 - Mudgal, Poorva A1 - Langefeld, Carl D A1 - Keene, Keith L A1 - Freedman, Barry I A1 - Mychaleckyj, Josyf C A1 - Nayak, Uma A1 - Raffel, Leslie J A1 - Goodarzi, Mark O A1 - Chen, Y-D Ida A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Sims, Mario A1 - Couper, David A1 - Pankow, James S A1 - Boerwinkle, Eric A1 - Adeyemo, Adebowale A1 - Doumatey, Ayo A1 - Chen, Guanjie A1 - Mathias, Rasika A A1 - Vaidya, Dhananjay A1 - Singleton, Andrew B A1 - Zonderman, Alan B A1 - Igo, Robert P A1 - Sedor, John R A1 - Kabagambe, Edmond K A1 - Siscovick, David S A1 - McKnight, Barbara A1 - Rice, Kenneth A1 - Liu, Yongmei A1 - Hsueh, Wen-Chi A1 - Zhao, Wei A1 - Bielak, Lawrence F A1 - Kraja, Aldi A1 - Province, Michael A A1 - Bottinger, Erwin P A1 - Gottesman, Omri A1 - Cai, Qiuyin A1 - Zheng, Wei A1 - Blot, William J A1 - Lowe, William L A1 - Pacheco, Jennifer A A1 - Crawford, Dana C A1 - Grundberg, Elin A1 - Rich, Stephen S A1 - Hayes, M Geoffrey A1 - Shu, Xiao-Ou A1 - Loos, Ruth J F A1 - Borecki, Ingrid B A1 - Peyser, Patricia A A1 - Cummings, Steven R A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Iyengar, Sudha K A1 - Evans, Michele K A1 - Becker, Diane M A1 - Kao, W H Linda A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Sale, Michèle M A1 - Liu, Simin A1 - Rotimi, Charles N A1 - Bowden, Donald W KW - African Americans KW - Diabetes Mellitus, Type 2 KW - Genome-Wide Association Study KW - HLA-B27 Antigen KW - HMGA2 Protein KW - Humans KW - KCNQ1 Potassium Channel KW - Mutant Chimeric Proteins KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

Type 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) VL - 10 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25102180?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of loci associated with age at natural menopause in African-American women. JF - Hum Mol Genet Y1 - 2014 A1 - Chen, Christina T L A1 - Liu, Ching-Ti A1 - Chen, Gary K A1 - Andrews, Jeanette S A1 - Arnold, Alice M A1 - Dreyfus, Jill A1 - Franceschini, Nora A1 - Garcia, Melissa E A1 - Kerr, Kathleen F A1 - Li, Guo A1 - Lohman, Kurt K A1 - Musani, Solomon K A1 - Nalls, Michael A A1 - Raffel, Leslie J A1 - Smith, Jennifer A1 - Ambrosone, Christine B A1 - Bandera, Elisa V A1 - Bernstein, Leslie A1 - Britton, Angela A1 - Brzyski, Robert G A1 - Cappola, Anne A1 - Carlson, Christopher S A1 - Couper, David A1 - Deming, Sandra L A1 - Goodarzi, Mark O A1 - Heiss, Gerardo A1 - John, Esther M A1 - Lu, Xiaoning A1 - Le Marchand, Loïc A1 - Marciante, Kristin A1 - McKnight, Barbara A1 - Millikan, Robert A1 - Nock, Nora L A1 - Olshan, Andrew F A1 - Press, Michael F A1 - Vaiyda, Dhananjay A1 - Woods, Nancy F A1 - Taylor, Herman A A1 - Zhao, Wei A1 - Zheng, Wei A1 - Evans, Michele K A1 - Harris, Tamara B A1 - Henderson, Brian E A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Yongmei A1 - Mosley, Thomas H A1 - Psaty, Bruce A1 - Wellons, Melissa A1 - Windham, Beverly G A1 - Zonderman, Alan B A1 - Cupples, L Adrienne A1 - Demerath, Ellen W A1 - Haiman, Christopher A1 - Murabito, Joanne M A1 - Rajkovic, Aleksandar KW - African Americans KW - Age Factors KW - Chromosomes, Human KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Menopause KW - United States AB -

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.

VL - 23 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24493794?dopt=Abstract ER - TY - JOUR T1 - Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Kocarnik, Jonathan M A1 - Pendergrass, Sarah A A1 - Carty, Cara L A1 - Pankow, James S A1 - Schumacher, Fredrick R A1 - Cheng, Iona A1 - Durda, Peter A1 - Ambite, Jose Luis A1 - Deelman, Ewa A1 - Cook, Nancy R A1 - Liu, Simin A1 - Wactawski-Wende, Jean A1 - Hutter, Carolyn A1 - Brown-Gentry, Kristin A1 - Wilson, Sarah A1 - Best, Lyle G A1 - Pankratz, Nathan A1 - Hong, Ching-Ping A1 - Cole, Shelley A A1 - Voruganti, V Saroja A1 - Bůzková, Petra A1 - Jorgensen, Neal W A1 - Jenny, Nancy S A1 - Wilkens, Lynne R A1 - Haiman, Christopher A A1 - Kolonel, Laurence N A1 - LaCroix, Andrea A1 - North, Kari A1 - Jackson, Rebecca A1 - Le Marchand, Loïc A1 - Hindorff, Lucia A A1 - Crawford, Dana C A1 - Gross, Myron A1 - Peters, Ulrike KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Asian Continental Ancestry Group KW - C-Reactive Protein KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Inflammation KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - United States KW - Young Adult AB -

BACKGROUND: 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.

VL - 7 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24622110?dopt=Abstract ER - TY - JOUR T1 - Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. JF - Stroke Y1 - 2014 A1 - Malik, Rainer A1 - Bevan, Steve A1 - Nalls, Michael A A1 - Holliday, Elizabeth G A1 - Devan, William J A1 - Cheng, Yu-Ching A1 - Ibrahim-Verbaas, Carla A A1 - Verhaaren, Benjamin F J A1 - Bis, Joshua C A1 - Joon, Aron Y A1 - de Stefano, Anita L A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Ikram, M Arfan A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Sharma, Pankaj A1 - Mitchell, Braxton D A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Levi, Christopher A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Dichgans, Martin KW - Adult KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Blood Pressure KW - Brain Ischemia KW - Case-Control Studies KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Multilocus Sequence Typing KW - Polymorphism, Single Nucleotide KW - Population KW - Prospective Studies KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Stroke AB -

BACKGROUND 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.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract ER - TY - JOUR T1 - No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. JF - PLoS One Y1 - 2014 A1 - Baumert, Jens A1 - Huang, Jie A1 - McKnight, Barbara A1 - Sabater-Lleal, Maria A1 - Steri, Maristella A1 - Chu, Audrey Y A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Fornage, Myriam A1 - Teumer, Alexander A1 - Tang, Weihong A1 - Rudnicka, Alicja R A1 - Mälarstig, Anders A1 - Hottenga, Jouke-Jan A1 - Kavousi, Maryam A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Hayward, Caroline A1 - Huffman, Jennifer E A1 - Morange, Pierre-Emmanuel A1 - Rose, Lynda M A1 - Basu, Saonli A1 - Rumley, Ann A1 - Stott, David J A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Sanna, Serena A1 - Masala, Marco A1 - Biffar, Reiner A1 - Homuth, Georg A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Goel, Anuj A1 - Watkins, Hugh A1 - Müller-Nurasyid, Martina A1 - Rückerl, Regina A1 - Taylor, Kent A1 - Chen, Ming-Huei A1 - de Geus, Eco J C A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - de Maat, Moniek P M A1 - Palotie, Aarno A1 - Davies, Gail A1 - Siscovick, David S A1 - Kolcic, Ivana A1 - Wild, Sarah H A1 - Song, Jaejoon A1 - McArdle, Wendy L A1 - Ford, Ian A1 - Sattar, Naveed A1 - Schlessinger, David A1 - Grotevendt, Anne A1 - Franzosi, Maria Grazia A1 - Illig, Thomas A1 - Waldenberger, Melanie A1 - Lumley, Thomas A1 - Tofler, Geoffrey H A1 - Willemsen, Gonneke A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Räikkönen, Katri A1 - Chasman, Daniel I A1 - Folsom, Aaron R A1 - Lowe, Gordon D A1 - Westendorp, Rudi G J A1 - Slagboom, P Eline A1 - Cucca, Francesco A1 - Wallaschofski, Henri A1 - Strawbridge, Rona J A1 - Seedorf, Udo A1 - Koenig, Wolfgang A1 - Bis, Joshua C A1 - Mukamal, Kenneth J A1 - van Dongen, Jenny A1 - Widen, Elisabeth A1 - Franco, Oscar H A1 - Starr, John M A1 - Liu, Kiang A1 - Ferrucci, Luigi A1 - Polasek, Ozren A1 - Wilson, James F A1 - Oudot-Mellakh, Tiphaine A1 - Campbell, Harry A1 - Navarro, Pau A1 - Bandinelli, Stefania A1 - Eriksson, Johan A1 - Boomsma, Dorret I A1 - Dehghan, Abbas A1 - Clarke, Robert A1 - Hamsten, Anders A1 - Boerwinkle, Eric A1 - Jukema, J Wouter A1 - Naitza, Silvia A1 - Ridker, Paul M A1 - Völzke, Henry A1 - Deary, Ian J A1 - Reiner, Alexander P A1 - Trégouët, David-Alexandre A1 - O'Donnell, Christopher J A1 - Strachan, David P A1 - Peters, Annette A1 - Smith, Nicholas L KW - Alcohol Drinking KW - Body Mass Index KW - Fibrinogen KW - Gene-Environment Interaction KW - Genomics KW - Humans KW - Smoking AB -

Plasma 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.

VL - 9 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract ER - TY - JOUR T1 - Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults. JF - Cytokine Y1 - 2014 A1 - Matteini, A M A1 - Li, J A1 - Lange, E M A1 - Tanaka, T A1 - Lange, L A A1 - Tracy, R P A1 - Wang, Y A1 - Biggs, M L A1 - Arking, D E A1 - Fallin, M D A1 - Chakravarti, A A1 - Psaty, B M A1 - Bandinelli, S A1 - Ferrucci, L A1 - Reiner, A P A1 - Walston, J D KW - Aged KW - Aged, 80 and over KW - Calcium-Binding Proteins KW - CARD Signaling Adaptor Proteins KW - Chromosomes, Human, Pair 2 KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Haplotypes KW - Humans KW - Inflammation KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-18 KW - Male KW - Polymorphism, Single Nucleotide AB -

Activation 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.

VL - 65 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24182552?dopt=Abstract ER - TY - JOUR T1 - Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. JF - J Am Coll Cardiol Y1 - 2014 A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Trompet, Stella A1 - Li, Guo A1 - Krijthe, Bouwe P A1 - Chasman, Daniel I A1 - Barnard, John A1 - Kleber, Marcus E A1 - Dörr, Marcus A1 - Ozaki, Kouichi A1 - Smith, Albert V A1 - Müller-Nurasyid, Martina A1 - Walter, Stefan A1 - Agarwal, Sunil K A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Chen, Lin Y A1 - Everett, Brendan M A1 - Ford, Ian A1 - Franco, Oscar H A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Kääb, Stefan A1 - Mahida, Saagar A1 - Kathiresan, Sekar A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - McKnight, Barbara A1 - McManus, David D A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Silbernagel, Guenther A1 - Smith, Jonathan D A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Taylor, Kent D A1 - Tomaschitz, Andreas A1 - Tsunoda, Tatsuhiko A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Murabito, Joanne M A1 - Sinner, Moritz F A1 - Gudnason, Vilmundur A1 - Felix, Stephan B A1 - März, Winfried A1 - Chung, Mina A1 - Albert, Christine M A1 - Stricker, Bruno H A1 - Tanaka, Toshihiro A1 - Heckbert, Susan R A1 - Jukema, J Wouter A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Ellinor, Patrick T KW - Adult KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Atrial Fibrillation KW - Chromosome Mapping KW - Chromosomes, Human, Pair 4 KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Homeodomain Proteins KW - Humans KW - Japan KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factors AB -

OBJECTIVES: 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.

VL - 63 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24486271?dopt=Abstract ER - TY - JOUR T1 - Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. JF - Nat Commun Y1 - 2014 A1 - Postmus, Iris A1 - Trompet, Stella A1 - Deshmukh, Harshal A A1 - Barnes, Michael R A1 - Li, Xiaohui A1 - Warren, Helen R A1 - Chasman, Daniel I A1 - Zhou, Kaixin A1 - Arsenault, Benoit J A1 - Donnelly, Louise A A1 - Wiggins, Kerri L A1 - Avery, Christy L A1 - Griffin, Paula A1 - Feng, QiPing A1 - Taylor, Kent D A1 - Li, Guo A1 - Evans, Daniel S A1 - Smith, Albert V A1 - de Keyser, Catherine E A1 - Johnson, Andrew D A1 - de Craen, Anton J M A1 - Stott, David J A1 - Buckley, Brendan M A1 - Ford, Ian A1 - Westendorp, Rudi G J A1 - Slagboom, P Eline A1 - Sattar, Naveed A1 - Munroe, Patricia B A1 - Sever, Peter A1 - Poulter, Neil A1 - Stanton, Alice A1 - Shields, Denis C A1 - O'Brien, Eoin A1 - Shaw-Hawkins, Sue A1 - Chen, Y-D Ida A1 - Nickerson, Deborah A A1 - Smith, Joshua D A1 - Dubé, Marie Pierre A1 - Boekholdt, S Matthijs A1 - Hovingh, G Kees A1 - Kastelein, John J P A1 - McKeigue, Paul M A1 - Betteridge, John A1 - Neil, Andrew A1 - Durrington, Paul N A1 - Doney, Alex A1 - Carr, Fiona A1 - Morris, Andrew A1 - McCarthy, Mark I A1 - Groop, Leif A1 - Ahlqvist, Emma A1 - Bis, Joshua C A1 - Rice, Kenneth A1 - Smith, Nicholas L A1 - Lumley, Thomas A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Boerwinkle, Eric A1 - Ngwa, Julius S A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - Wei, Wei-Qi A1 - Wilke, Russell A A1 - Liu, Ching-Ti A1 - Sun, Fangui A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Post, Wendy A1 - Sotoodehnia, Nona A1 - Arnold, Alice M A1 - Stafford, Jeanette M A1 - Ding, Jingzhong A1 - Herrington, David M A1 - Kritchevsky, Stephen B A1 - Eiriksdottir, Gudny A1 - Launer, Leonore J A1 - Harris, Tamara B A1 - Chu, Audrey Y A1 - Giulianini, Franco A1 - MacFadyen, Jean G A1 - Barratt, Bryan J A1 - Nyberg, Fredrik A1 - Stricker, Bruno H A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Emilsson, Valur A1 - Franco, Oscar H A1 - Ridker, Paul M A1 - Gudnason, Vilmundur A1 - Liu, Yongmei A1 - Denny, Joshua C A1 - Ballantyne, Christie M A1 - Rotter, Jerome I A1 - Adrienne Cupples, L A1 - Psaty, Bruce M A1 - Palmer, Colin N A A1 - Tardif, Jean-Claude A1 - Colhoun, Helen M A1 - Hitman, Graham A1 - Krauss, Ronald M A1 - Wouter Jukema, J A1 - Caulfield, Mark J KW - Cholesterol, LDL KW - Genome-Wide Association Study KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide AB -

Statins 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.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract ER - TY - JOUR T1 - Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study. JF - Br J Nutr Y1 - 2014 A1 - Fretts, Amanda M A1 - Mozaffarian, Dariush A1 - Siscovick, David S A1 - Sitlani, Colleen A1 - Psaty, Bruce M A1 - Rimm, Eric B A1 - Song, Xiaoling A1 - McKnight, Barbara A1 - Spiegelman, Donna A1 - King, Irena B A1 - Lemaitre, Rozenn N KW - Aged KW - alpha-Linolenic Acid KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Diet KW - Female KW - Humans KW - Male KW - Mortality KW - Phospholipids KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

Previous 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.

VL - 112 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25159901?dopt=Abstract ER - TY - JOUR T1 - Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2014 A1 - Miedema, Michael D A1 - Maziarz, Marlena A1 - Biggs, Mary L A1 - Zieman, Susan J A1 - Kizer, Jorge R A1 - Ix, Joachim H A1 - Mozaffarian, Dariush A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Mukamal, Kenneth J A1 - Djoussé, Luc KW - Age Distribution KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Cause of Death KW - Fatty Acid-Binding Proteins KW - Fatty Acids, Nonesterified KW - Female KW - Follow-Up Studies KW - Health Status KW - Humans KW - Male KW - Prognosis KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Survival Rate KW - Time Factors KW - United States AB -

Plasma-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.

VL - 114 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25073566?dopt=Abstract ER - TY - JOUR T1 - Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. JF - Stroke Y1 - 2014 A1 - Ibrahim-Verbaas, Carla A A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Choi, Seung Hoan A1 - Psaty, Bruce M A1 - Meigs, James B A1 - Rao, Madhu A1 - Nalls, Mike A1 - Fontes, João D A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Ehret, Georg B A1 - Fox, Caroline S A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Schmidt, Helena A1 - Lahti, Jari A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Folsom, Aaron R A1 - Boerwinkle, Eric A1 - Rosamond, Wayne D A1 - Shahar, Eyal A1 - Gottesman, Rebecca F A1 - Koudstaal, Peter J A1 - Amin, Najaf A1 - Wieberdink, Renske G A1 - Dehghan, Abbas A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - DeStefano, Anita L A1 - Debette, Stephanie A1 - Xue, Luting A1 - Beiser, Alexa A1 - Wolf, Philip A A1 - DeCarli, Charles A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Area Under Curve KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - ROC Curve KW - Sex Factors KW - Stroke AB -

BACKGROUND 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.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract ER - TY - JOUR T1 - Prognostic implications of microvascular and macrovascular abnormalities in older adults: cardiovascular health study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Kim, Dae Hyun A1 - Grodstein, Francine A1 - Newman, Anne B A1 - Chaves, Paulo H M A1 - Odden, Michelle C A1 - Klein, Ronald A1 - Sarnak, Mark J A1 - Patel, Kushang V A1 - Lipsitz, Lewis A KW - Aged KW - Aged, 80 and over KW - Aging KW - Ankle Brachial Index KW - Disability Evaluation KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Forecasting KW - Humans KW - Life Expectancy KW - Magnetic Resonance Imaging KW - Male KW - Microcirculation KW - Prognosis KW - Prospective Studies KW - Risk Factors KW - Vascular Malformations AB -

BACKGROUND: 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.

VL - 69 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24864308?dopt=Abstract ER - TY - JOUR T1 - Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. JF - Hum Mol Genet Y1 - 2014 A1 - Gordon, Adam S A1 - Tabor, Holly K A1 - Johnson, Andrew D A1 - Snively, Beverly M A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Ioannidis, John P A A1 - Peters, Ulrike A1 - Robinson, Jennifer G A1 - Sucheston, Lara E A1 - Wang, Danxin A1 - Sotoodehnia, Nona A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Jackson, Rebecca D A1 - Herrington, David M A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rieder, Mark J A1 - Bamshad, Michael J A1 - Nickerson, Deborah A KW - Cytochrome P-450 Enzyme System KW - Databases, Genetic KW - European Continental Ancestry Group KW - Exome KW - Humans KW - Pharmaceutical Preparations KW - Pharmacogenetics KW - Polymorphism, Genetic AB -

The 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.

VL - 23 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24282029?dopt=Abstract ER - TY - JOUR T1 - Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar. JF - Kidney Int Y1 - 2014 A1 - Wen, Chi Pang A1 - Matsushita, Kunihiro A1 - Coresh, Josef A1 - Iseki, Kunitoshi A1 - Islam, Muhammad A1 - Katz, Ronit A1 - McClellan, William A1 - Peralta, Carmen A A1 - Wang, Haiyan A1 - de Zeeuw, Dick A1 - Astor, Brad C A1 - Gansevoort, Ron T A1 - Levey, Andrew S A1 - Levin, Adeera KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Asian Continental Ancestry Group KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Odds Ratio KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

Some 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.

VL - 86 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24522492?dopt=Abstract ER - TY - JOUR T1 - Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2014 A1 - Odden, Michelle C A1 - Shlipak, Michael G A1 - Whitson, Heather E A1 - Katz, Ronit A1 - Kearney, Patricia M A1 - deFilippi, Chris A1 - Shastri, Shani A1 - Sarnak, Mark J A1 - Siscovick, David S A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Complications KW - Diabetes Mellitus KW - Female KW - Humans KW - Inflammation KW - Kidney KW - Kidney Diseases KW - Lipids KW - Male KW - Natriuretic Peptide, Brain KW - Obesity KW - Peptide Fragments KW - Risk Factors AB -

OBJECTIVE: 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.

VL - 237 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25303772?dopt=Abstract ER - TY - JOUR T1 - Separate prediction of intracerebral hemorrhage and ischemic stroke. JF - Neurology Y1 - 2014 A1 - Ferket, Bart S A1 - van Kempen, Bob J H A1 - Wieberdink, Renske G A1 - Steyerberg, Ewout W A1 - Koudstaal, Peter J A1 - Hofman, Albert A1 - Shahar, Eyal A1 - Gottesman, Rebecca F A1 - Rosamond, Wayne A1 - Kizer, Jorge R A1 - Kronmal, Richard A A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Mosley, Thomas A1 - Folsom, Aaron R A1 - Hunink, M G Myriam A1 - Ikram, M Arfan KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Body Mass Index KW - Brain Ischemia KW - Cholesterol KW - Female KW - Humans KW - Incidence KW - Intracranial Hemorrhages KW - Male KW - Middle Aged KW - Models, Statistical KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - Stroke AB -

OBJECTIVES: 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.

VL - 82 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24759844?dopt=Abstract ER - TY - JOUR T1 - Sequence 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. JF - PLoS One Y1 - 2014 A1 - Morrison, Alanna C A1 - Bis, Joshua C A1 - Hwang, Shih-Jen A1 - Ehret, Georg B A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Chakravarti, Aravinda A1 - Levy, Daniel KW - Aging KW - Blood Pressure KW - Cohort Studies KW - Heart KW - Humans KW - Sequence Analysis AB -

BACKGROUND: 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.

VL - 9 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25275628?dopt=Abstract ER - TY - JOUR T1 - Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Bis, Joshua C A1 - White, Charles C A1 - Franceschini, Nora A1 - Brody, Jennifer A1 - Zhang, Xiaoling A1 - Muzny, Donna A1 - Santibanez, Jireh A1 - Gibbs, Richard A1 - Liu, Xiaoming A1 - Lin, Honghuang A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - North, Kari E A1 - Cupples, L Adrienne A1 - O'Donnell, Christopher J KW - Aged KW - Aged, 80 and over KW - Aging KW - Atherosclerosis KW - Class Ib Phosphatidylinositol 3-Kinase KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA KW - Sodium-Phosphate Cotransporter Proteins, Type I AB -

BACKGROUND: 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.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951662?dopt=Abstract ER - TY - JOUR T1 - Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Magnani, Jared W A1 - Brody, Jennifer A A1 - Prins, Bram P A1 - Arking, Dan E A1 - Lin, Honghuang A1 - Yin, Xiaoyan A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Zhang, Feng A1 - Spector, Tim D A1 - Alonso, Alvaro A1 - Bis, Joshua C A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Sitlani, Colleen M A1 - Cupples, L Adrienne A1 - Lubitz, Steven A A1 - Soliman, Elsayed Z A1 - Pulit, Sara L A1 - Newton-Cheh, Christopher A1 - O'Donnell, Christopher J A1 - Ellinor, Patrick T A1 - Benjamin, Emelia J A1 - Muzny, Donna M A1 - Gibbs, Richard A A1 - Santibanez, Jireh A1 - Taylor, Herman A A1 - Rotter, Jerome I A1 - Lange, Leslie A A1 - Psaty, Bruce M A1 - Jackson, Rebecca A1 - Rich, Stephen S A1 - Boerwinkle, Eric A1 - Jamshidi, Yalda A1 - Sotoodehnia, Nona KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Conduction System KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951663?dopt=Abstract ER - TY - JOUR T1 - Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. JF - Stroke Y1 - 2014 A1 - Dichgans, Martin A1 - Malik, Rainer A1 - König, Inke R A1 - Rosand, Jonathan A1 - Clarke, Robert A1 - Gretarsdottir, Solveig A1 - Thorleifsson, Gudmar A1 - Mitchell, Braxton D A1 - Assimes, Themistocles L A1 - Levi, Christopher A1 - O'Donnell, Christopher J A1 - Fornage, Myriam A1 - Thorsteinsdottir, Unnur A1 - Psaty, Bruce M A1 - Hengstenberg, Christian A1 - Seshadri, Sudha A1 - Erdmann, Jeanette A1 - Bis, Joshua C A1 - Peters, Annette A1 - Boncoraglio, Giorgio B A1 - März, Winfried A1 - Meschia, James F A1 - Kathiresan, Sekar A1 - Ikram, M Arfan A1 - McPherson, Ruth A1 - Stefansson, Kari A1 - Sudlow, Cathie A1 - Reilly, Muredach P A1 - Thompson, John R A1 - Sharma, Pankaj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Watkins, Hugh A1 - Rothwell, Peter M A1 - Roberts, Robert A1 - Markus, Hugh S A1 - Samani, Nilesh J A1 - Farrall, Martin A1 - Schunkert, Heribert KW - Brain Ischemia KW - Coronary Artery Disease KW - Data Interpretation, Statistical KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results KW - Risk Factors KW - Stroke AB -

BACKGROUND 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.

VL - 45 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24262325?dopt=Abstract ER - TY - JOUR T1 - Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Varadhan, Ravi A1 - Yao, Wenliang A1 - Matteini, Amy A1 - Beamer, Brock A A1 - Xue, Qian-Li A1 - Yang, Huanle A1 - Manwani, Bhavish A1 - Reiner, Alexander A1 - Jenny, Nancy A1 - Parekh, Neel A1 - Fallin, M Daniele A1 - Newman, Anne A1 - Bandeen-Roche, Karen A1 - Tracy, Russell A1 - Ferrucci, Luigi A1 - Walston, Jeremy KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Cohort Studies KW - Female KW - Humans KW - Inflammation KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-18 KW - Interleukin-6 KW - Longevity KW - Male KW - Receptors, Tumor Necrosis Factor, Type I KW - Risk Factors AB -

BACKGROUND: 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.

VL - 69 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23689826?dopt=Abstract ER - TY - JOUR T1 - Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes. JF - Diabetologia Y1 - 2014 A1 - Tare, Archana A1 - Lane, Jacqueline M A1 - Cade, Brian E A1 - Grant, Struan F A A1 - Chen, Ting-Hsu A1 - Punjabi, Naresh M A1 - Lauderdale, Diane S A1 - Zee, Phyllis C A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Scheer, Frank A J L A1 - Redline, Susan A1 - Saxena, Richa KW - Blood Glucose KW - Body Composition KW - Body Mass Index KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Glucose Intolerance KW - Glycated Hemoglobin A KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sleep KW - Surveys and Questionnaires KW - Time Factors KW - United States AB -

AIMS/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.

VL - 57 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24280871?dopt=Abstract ER - TY - JOUR T1 - Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Lin, Honghuang A1 - Wang, Min A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Dupuis, Josée A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Rice, Kenneth M A1 - Sitlani, Colleen M A1 - Reid, Jeffrey G A1 - Bressler, Jan A1 - Liu, Xiaoming A1 - Davis, Brian C A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Kovar, Christie L A1 - Dinh, Huyen A1 - Wu, Yuanqing A1 - Newsham, Irene A1 - Chen, Han A1 - Broka, Andi A1 - DeStefano, Anita L A1 - Gupta, Mayetri A1 - Lunetta, Kathryn L A1 - Liu, Ching-Ti A1 - White, Charles C A1 - Xing, Chuanhua A1 - Zhou, Yanhua A1 - Benjamin, Emelia J A1 - Schnabel, Renate B A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Muzny, Donna M A1 - Cupples, L Adrienne A1 - Morrison, Alanna C A1 - Boerwinkle, Eric KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Research Design KW - Sequence Analysis, DNA AB -

BACKGROUND: 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.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951659?dopt=Abstract ER - TY - JOUR T1 - Systolic and diastolic blood pressure, incident cardiovascular events, and death in elderly persons: the role of functional limitation in the Cardiovascular Health Study. JF - Hypertension Y1 - 2014 A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Odden, Michelle C KW - Activities of Daily Living KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gait KW - Heart Rate KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Risk Factors KW - Survival Rate KW - Systole AB -

Whether 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.

VL - 64 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24935945?dopt=Abstract ER - TY - JOUR T1 - Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. JF - Heart Rhythm Y1 - 2014 A1 - Lin, Honghuang A1 - Sinner, Moritz F A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Lunetta, Kathryn L A1 - Rienstra, Michiel A1 - Lubitz, Steven A A1 - Magnani, Jared W A1 - Sotoodehnia, Nona A1 - McKnight, Barbara A1 - McManus, David D A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Gibbs, Richard A A1 - Muzny, Donna A1 - Kovar, Christie L A1 - Morrison, Alanna C A1 - Gupta, Mayetri A1 - Folsom, Aaron R A1 - Kääb, Stefan A1 - Heckbert, Susan R A1 - Alonso, Alvaro A1 - Ellinor, Patrick T A1 - Benjamin, Emelia J KW - Aged KW - Atrial Fibrillation KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Homeodomain Proteins KW - Humans KW - Linkage Disequilibrium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 AB -

BACKGROUND: 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.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24239840?dopt=Abstract ER - TY - JOUR T1 - Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging. JF - Circ Arrhythm Electrophysiol Y1 - 2014 A1 - Roberts, Jason D A1 - Dewland, Thomas A A1 - Longoria, James A1 - Fitzpatrick, Annette L A1 - Ziv, Elad A1 - Hu, Donglei A1 - Lin, Jue A1 - Glidden, David V A1 - Psaty, Bruce M A1 - Burchard, Esteban G A1 - Blackburn, Elizabeth H A1 - Olgin, Jeffrey E A1 - Heckbert, Susan R A1 - Marcus, Gregory M KW - Age Factors KW - Aged KW - Aging KW - Atrial Fibrillation KW - California KW - Cardiac Surgical Procedures KW - Cellular Senescence KW - Cross-Sectional Studies KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Incidence KW - Leukocytes KW - Male KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Telomerase KW - Telomere KW - Time Factors AB -

BACKGROUND: 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.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25381796?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic meta-analysis of white blood cell phenotypes. JF - Hum Mol Genet Y1 - 2014 A1 - Keller, Margaux F A1 - Reiner, Alexander P A1 - Okada, Yukinori A1 - van Rooij, Frank J A A1 - Johnson, Andrew D A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Morris, Andrew P A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Zonderman, Alan B A1 - Lettre, Guillaume A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Bandinelli, Stefania A1 - Qayyum, Rehan A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Kooperberg, Charles A1 - Keating, Brendan A1 - Reis, Jared A1 - Tang, Hua A1 - Boerwinkle, Eric A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Nakamura, Yusuke A1 - Kubo, Michiaki A1 - Liu, Simin A1 - Dehghan, Abbas A1 - Felix, Janine F A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Longo, Dan L A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Evans, Michelle K A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Takahashi, Atsushi A1 - Wilson, James G A1 - Ganesh, Santhi K A1 - Nalls, Mike A KW - African Americans KW - Asian Continental Ancestry Group KW - Bayes Theorem KW - European Continental Ancestry Group KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Linkage Disequilibrium KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

White 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.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract ER - TY - JOUR T1 - What do carotid intima-media thickness and plaque add to the prediction of stroke and cardiovascular disease risk in older adults? The cardiovascular health study. JF - J Am Soc Echocardiogr Y1 - 2014 A1 - Gardin, Julius M A1 - Bartz, Traci M A1 - Polak, Joseph F A1 - O'Leary, Daniel H A1 - Wong, Nathan D KW - Aged KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Carotid Stenosis KW - Comorbidity KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Reproducibility of Results KW - Risk Factors KW - Sensitivity and Specificity KW - Stroke KW - Survival Rate AB -

BACKGROUND: 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.

VL - 27 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25172401?dopt=Abstract ER - TY - JOUR T1 - Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. JF - Am J Hum Genet Y1 - 2014 A1 - Lange, Leslie A A1 - Hu, Youna A1 - Zhang, He A1 - Xue, Chenyi A1 - Schmidt, Ellen M A1 - Tang, Zheng-Zheng A1 - Bizon, Chris A1 - Lange, Ethan M A1 - Smith, Joshua D A1 - Turner, Emily H A1 - Jun, Goo A1 - Kang, Hyun Min A1 - Peloso, Gina A1 - Auer, Paul A1 - Li, Kuo-Ping A1 - Flannick, Jason A1 - Zhang, Ji A1 - Fuchsberger, Christian A1 - Gaulton, Kyle A1 - Lindgren, Cecilia A1 - Locke, Adam A1 - Manning, Alisa A1 - Sim, Xueling A1 - Rivas, Manuel A A1 - Holmen, Oddgeir L A1 - Gottesman, Omri A1 - Lu, Yingchang A1 - Ruderfer, Douglas A1 - Stahl, Eli A A1 - Duan, Qing A1 - Li, Yun A1 - Durda, Peter A1 - Jiao, Shuo A1 - Isaacs, Aaron A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Jakobsdottir, Johanna A1 - Smith, Albert V A1 - Schreiner, Pamela J A1 - Feitosa, Mary F A1 - Zhang, Qunyuan A1 - Huffman, Jennifer E A1 - Crosby, Jacy A1 - Wassel, Christina L A1 - Do, Ron A1 - Franceschini, Nora A1 - Martin, Lisa W A1 - Robinson, Jennifer G A1 - Assimes, Themistocles L A1 - Crosslin, David R A1 - Rosenthal, Elisabeth A A1 - Tsai, Michael A1 - Rieder, Mark J A1 - Farlow, Deborah N A1 - Folsom, Aaron R A1 - Lumley, Thomas A1 - Fox, Ervin R A1 - Carlson, Christopher S A1 - Peters, Ulrike A1 - Jackson, Rebecca D A1 - van Duijn, Cornelia M A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fornage, Myriam A1 - Borecki, Ingrid B A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Chen, Y Eugene A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Sætrom, Pål A1 - Hveem, Kristian A1 - Boehnke, Michael A1 - Groop, Leif A1 - McCarthy, Mark A1 - Meitinger, Thomas A1 - Ballantyne, Christie M A1 - Gabriel, Stacey B A1 - O'Donnell, Christopher J A1 - Post, Wendy S A1 - North, Kari E A1 - Reiner, Alexander P A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Altshuler, David A1 - Kathiresan, Sekar A1 - Lin, Dan-Yu A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Kooperberg, Charles A1 - Wilson, James G A1 - Nickerson, Deborah A A1 - Abecasis, Goncalo R A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Willer, Cristen J KW - Adult KW - Aged KW - Apolipoproteins E KW - Cholesterol, LDL KW - Cohort Studies KW - Dyslipidemias KW - Exome KW - Female KW - Follow-Up Studies KW - Gene Frequency KW - Genetic Code KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipase KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proprotein Convertase 9 KW - Proprotein Convertases KW - Receptors, LDL KW - Sequence Analysis, DNA KW - Serine Endopeptidases AB -

Elevated 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.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract ER - TY - JOUR T1 - Association between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study. JF - Stroke Y1 - 2015 A1 - Kamel, Hooman A1 - Bartz, Traci M A1 - Longstreth, W T A1 - Okin, Peter M A1 - Thacker, Evan L A1 - Patton, Kristen K A1 - Stein, Phyllis K A1 - Gottesman, Rebecca F A1 - Heckbert, Susan R A1 - Kronmal, Richard A A1 - Elkind, Mitchell S V A1 - Soliman, Elsayed Z KW - Aged KW - Atrial Fibrillation KW - Brain KW - Brain Infarction KW - Cardiovascular Diseases KW - Cerebrovascular Trauma KW - Electrocardiography KW - Female KW - Heart Atria KW - Heart Diseases KW - Humans KW - Linear Models KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Treatment Outcome AB -

BACKGROUND 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.

VL - 46 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25677594?dopt=Abstract ER - TY - JOUR T1 - Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. JF - Respir Res Y1 - 2015 A1 - Hansen, J G A1 - Gao, W A1 - Dupuis, J A1 - O'Connor, G T A1 - Tang, W A1 - Kowgier, M A1 - Sood, A A1 - Gharib, S A A1 - Palmer, L J A1 - Fornage, M A1 - Heckbert, S R A1 - Psaty, B M A1 - Booth, S L A1 - Cassano, Patricia A KW - Adult KW - Aged KW - Cohort Studies KW - Cross-Sectional Studies KW - DNA-Binding Proteins KW - Female KW - Genetic Variation KW - Humans KW - Longitudinal Studies KW - Male KW - Massachusetts KW - Metabolic Networks and Pathways KW - Middle Aged KW - Nuclear Proteins KW - Polymorphism, Single Nucleotide KW - Vitamin D AB -

BACKGROUND: 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.

VL - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26122139?dopt=Abstract ER - TY - JOUR T1 - Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. JF - Neurobiol Aging Y1 - 2015 A1 - Chauhan, Ganesh A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Weinstein, Galit A1 - Yu, Lei A1 - Töglhofer, Anna Maria A1 - Smith, Albert Vernon A1 - van der Lee, Sven J A1 - Gottesman, Rebecca F A1 - Thomson, Russell A1 - Wang, Jing A1 - Yang, Qiong A1 - Niessen, Wiro J A1 - Lopez, Oscar L A1 - Becker, James T A1 - Phan, Thanh G A1 - Beare, Richard J A1 - Arfanakis, Konstantinos A1 - Fleischman, Debra A1 - Vernooij, Meike W A1 - Mazoyer, Bernard A1 - Schmidt, Helena A1 - Srikanth, Velandai A1 - Knopman, David S A1 - Jack, Clifford R A1 - Amouyel, Philippe A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Bennett, David A A1 - Schmidt, Reinhold A1 - Longstreth, William T A1 - Mosley, Thomas H A1 - Fornage, Myriam A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Debette, Stephanie KW - Aging KW - Alleles KW - Alzheimer Disease KW - Apolipoproteins E KW - Brain KW - Female KW - Genome-Wide Association Study KW - Hippocampus KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Organ Size KW - Polymorphism, Single Nucleotide KW - Risk KW - Sialic Acid Binding Ig-like Lectin 3 AB -

Whether 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.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract ER - TY - JOUR T1 - Association of Cardiometabolic Multimorbidity With Mortality. JF - JAMA Y1 - 2015 A1 - Di Angelantonio, Emanuele A1 - Kaptoge, Stephen A1 - Wormser, David A1 - Willeit, Peter A1 - Butterworth, Adam S A1 - Bansal, Narinder A1 - O'Keeffe, Linda M A1 - Gao, Pei A1 - Wood, Angela M A1 - Burgess, Stephen A1 - Freitag, Daniel F A1 - Pennells, Lisa A1 - Peters, Sanne A A1 - Hart, Carole L A1 - Håheim, Lise Lund A1 - Gillum, Richard F A1 - Nordestgaard, Børge G A1 - Psaty, Bruce M A1 - Yeap, Bu B A1 - Knuiman, Matthew W A1 - Nietert, Paul J A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Kuller, Lewis H A1 - Simons, Leon A A1 - van der Schouw, Yvonne T A1 - Barrett-Connor, Elizabeth A1 - Selmer, Randi A1 - Crespo, Carlos J A1 - Rodriguez, Beatriz A1 - Verschuren, W M Monique A1 - Salomaa, Veikko A1 - Svärdsudd, Kurt A1 - van der Harst, Pim A1 - Björkelund, Cecilia A1 - Wilhelmsen, Lars A1 - Wallace, Robert B A1 - Brenner, Hermann A1 - Amouyel, Philippe A1 - Barr, Elizabeth L M A1 - Iso, Hiroyasu A1 - Onat, Altan A1 - Trevisan, Maurizio A1 - D'Agostino, Ralph B A1 - Cooper, Cyrus A1 - Kavousi, Maryam A1 - Welin, Lennart A1 - Roussel, Ronan A1 - Hu, Frank B A1 - Sato, Shinichi A1 - Davidson, Karina W A1 - Howard, Barbara V A1 - Leening, Maarten J G A1 - Leening, Maarten A1 - Rosengren, Annika A1 - Dörr, Marcus A1 - Deeg, Dorly J H A1 - Kiechl, Stefan A1 - Stehouwer, Coen D A A1 - Nissinen, Aulikki A1 - Giampaoli, Simona A1 - Donfrancesco, Chiara A1 - Kromhout, Daan A1 - Price, Jackie F A1 - Peters, Annette A1 - Meade, Tom W A1 - Casiglia, Edoardo A1 - Lawlor, Debbie A A1 - Gallacher, John A1 - Nagel, Dorothea A1 - Franco, Oscar H A1 - Assmann, Gerd A1 - Dagenais, Gilles R A1 - Jukema, J Wouter A1 - Sundström, Johan A1 - Woodward, Mark A1 - Brunner, Eric J A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Whitsel, Eric A A1 - Njølstad, Inger A1 - Hedblad, Bo A1 - Wassertheil-Smoller, Sylvia A1 - Engström, Gunnar A1 - Rosamond, Wayne D A1 - Selvin, Elizabeth A1 - Sattar, Naveed A1 - Thompson, Simon G A1 - Danesh, John KW - Adult KW - Aged KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Humans KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality KW - Myocardial Infarction KW - Risk Factors KW - Stroke AB -

IMPORTANCE: 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.

VL - 314 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26151266?dopt=Abstract ER - TY - JOUR T1 - Association of exome sequences with plasma C-reactive protein levels in >9000 participants. JF - Hum Mol Genet Y1 - 2015 A1 - Schick, Ursula M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Lin, Honghuang A1 - Wei, Peng A1 - Pankratz, Nathan A1 - Lange, Leslie A A1 - Brody, Jennifer A1 - Stitziel, Nathan O A1 - Kim, Daniel S A1 - Carlson, Christopher S A1 - Fornage, Myriam A1 - Haessler, Jeffery A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Leal, Suzanne M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Tracy, Russell A1 - Ardissino, Diego A1 - Shah, Svati A1 - Willer, Cristen A1 - Loos, Ruth A1 - Melander, Olle A1 - McPherson, Ruth A1 - Hovingh, Kees A1 - Reilly, Muredach A1 - Watkins, Hugh A1 - Girelli, Domenico A1 - Fontanillas, Pierre A1 - Chasman, Daniel I A1 - Gabriel, Stacey B A1 - Gibbs, Richard A1 - Nickerson, Deborah A A1 - Kathiresan, Sekar A1 - Peters, Ulrike A1 - Dupuis, Josée A1 - Wilson, James G A1 - Rich, Stephen S A1 - Morrison, Alanna C A1 - Benjamin, Emelia J A1 - Gross, Myron D A1 - Reiner, Alex P KW - Adult KW - African Americans KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hepatocyte Nuclear Factor 1-alpha KW - Humans KW - Male KW - Plasma KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors AB -

C-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.

VL - 24 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract ER - TY - JOUR T1 - Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Yu, Bing A1 - Li, Alexander H A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - de Vries, Paul S A1 - Bis, Joshua C A1 - Musani, Solomon K A1 - Alexander, Danny A1 - Morrison, Alanna C A1 - Franco, Oscar H A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Dehghan, Abbas A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Gibbs, Richard A1 - Wei, Peng A1 - Boerwinkle, Eric KW - Adult KW - African Americans KW - Alleles KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Histidine KW - Histidine Ammonia-Lyase KW - Humans KW - Male KW - Mutation AB -

BACKGROUND: 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.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25575548?dopt=Abstract ER - TY - JOUR T1 - Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults. JF - J Am Geriatr Soc Y1 - 2015 A1 - Aneke-Nash, Chino S A1 - Parrinello, Christina M A1 - Rajpathak, Swapnil N A1 - Rohan, Thomas E A1 - Strotmeyer, Elsa S A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Bůzková, Petra A1 - Kizer, Jorge R A1 - Newman, Anne B A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Retrospective Studies AB -

OBJECTIVES: 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.

VL - 63 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25989565?dopt=Abstract ER - TY - JOUR T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. JF - Neurology Y1 - 2015 A1 - Rannikmae, Kristiina A1 - Davies, Gail A1 - Thomson, Pippa A A1 - Bevan, Steve A1 - Devan, William J A1 - Falcone, Guido J A1 - Traylor, Matthew A1 - Anderson, Christopher D A1 - Battey, Thomas W K A1 - Radmanesh, Farid A1 - Deka, Ranjan A1 - Woo, Jessica G A1 - Martin, Lisa J A1 - Jimenez-Conde, Jordi A1 - Selim, Magdy A1 - Brown, Devin L A1 - Silliman, Scott L A1 - Kidwell, Chelsea S A1 - Montaner, Joan A1 - Langefeld, Carl D A1 - Slowik, Agnieszka A1 - Hansen, Bjorn M A1 - Lindgren, Arne G A1 - Meschia, James F A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Debette, Stephanie A1 - Ikram, Mohammad A A1 - Longstreth, Will T A1 - Schmidt, Reinhold A1 - Zhang, Cathy R A1 - Yang, Qiong A1 - Sharma, Pankaj A1 - Kittner, Steven J A1 - Mitchell, Braxton D A1 - Holliday, Elizabeth G A1 - Levi, Christopher R A1 - Attia, John A1 - Rothwell, Peter M A1 - Poole, Deborah L A1 - Boncoraglio, Giorgio B A1 - Psaty, Bruce M A1 - Malik, Rainer A1 - Rost, Natalia A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Van Agtmael, Tom A1 - Woo, Daniel A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Rosand, Jonathan A1 - Sudlow, Cathie L M KW - Cerebral Small Vessel Diseases KW - Collagen Type IV KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide AB -

OBJECTIVES: 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.

VL - 84 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract ER - TY - JOUR T1 - Consumption 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. JF - Am J Clin Nutr Y1 - 2015 A1 - Fretts, Amanda M A1 - Follis, Jack L A1 - Nettleton, Jennifer A A1 - Lemaitre, Rozenn N A1 - Ngwa, Julius S A1 - Wojczynski, Mary K A1 - Kalafati, Ioanna Panagiota A1 - Varga, Tibor V A1 - Frazier-Wood, Alexis C A1 - Houston, Denise K A1 - Lahti, Jari A1 - Ericson, Ulrika A1 - van den Hooven, Edith H A1 - Mikkilä, Vera A1 - Kiefte-de Jong, Jessica C A1 - Mozaffarian, Dariush A1 - Rice, Kenneth A1 - Renstrom, Frida A1 - North, Kari E A1 - McKeown, Nicola M A1 - Feitosa, Mary F A1 - Kanoni, Stavroula A1 - Smith, Caren E A1 - Garcia, Melissa E A1 - Tiainen, Anna-Maija A1 - Sonestedt, Emily A1 - Manichaikul, Ani A1 - van Rooij, Frank J A A1 - Dimitriou, Maria A1 - Raitakari, Olli A1 - Pankow, James S A1 - Djoussé, Luc A1 - Province, Michael A A1 - Hu, Frank B A1 - Lai, Chao-Qiang A1 - Keller, Margaux F A1 - Perälä, Mia-Maria A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Graff, Misa A1 - Kähönen, Mika A1 - Mukamal, Kenneth A1 - Johansson, Ingegerd A1 - Ordovas, Jose M A1 - Liu, Yongmei A1 - Männistö, Satu A1 - Uitterlinden, André G A1 - Deloukas, Panos A1 - Seppälä, Ilkka A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Borecki, Ingrid B A1 - Franks, Paul W A1 - Arnett, Donna K A1 - Nalls, Mike A A1 - Eriksson, Johan G A1 - Orho-Melander, Marju A1 - Franco, Oscar H A1 - Lehtimäki, Terho A1 - Dedoussis, George V A1 - Meigs, James B A1 - Siscovick, David S KW - Blood Glucose KW - Cohort Studies KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hyperglycemia KW - Hyperinsulinism KW - Insulin KW - Insulin Resistance KW - Insulin-Secreting Cells KW - Meat KW - Meat Products KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: 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).

VL - 102 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26354543?dopt=Abstract ER - TY - JOUR T1 - Contribution of Major Lifestyle Risk Factors for Incident Heart Failure in Older Adults: The Cardiovascular Health Study. JF - JACC Heart Fail Y1 - 2015 A1 - Del Gobbo, Liana C A1 - Kalantarian, Shadi A1 - Imamura, Fumiaki A1 - Lemaitre, Rozenn A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Mozaffarian, Dariush KW - Aged KW - Alcohol Drinking KW - Cohort Studies KW - Diet KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Motor Activity KW - Obesity KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sedentary Lifestyle KW - Smoking KW - United States AB -

OBJECTIVES: 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.

VL - 3 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26160366?dopt=Abstract ER - TY - JOUR T1 - DCAF4, a novel gene associated with leucocyte telomere length. JF - J Med Genet Y1 - 2015 A1 - Mangino, Massimo A1 - Christiansen, Lene A1 - Stone, Rivka A1 - Hunt, Steven C A1 - Horvath, Kent A1 - Eisenberg, Dan T A A1 - Kimura, Masayuki A1 - Petersen, Inge A1 - Kark, Jeremy D A1 - Herbig, Utz A1 - Reiner, Alex P A1 - Benetos, Athanase A1 - Codd, Veryan A1 - Nyholt, Dale R A1 - Sinnreich, Ronit A1 - Christensen, Kaare A1 - Nassar, Hisham A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Bataille, Veronique A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Samani, Nilesh J A1 - Martin, Nicholas G A1 - Tishkoff, Sarah A1 - Schork, Nicholas J A1 - Kyvik, Kirsten Ohm A1 - Dalgård, Christine A1 - Spector, Timothy D A1 - Aviv, Abraham KW - Alleles KW - Carrier Proteins KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Humans KW - Leukocytes KW - Melanoma KW - Risk Factors KW - Telomere KW - Telomere Homeostasis AB -

BACKGROUND: 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.

VL - 52 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25624462?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD. JF - Clin J Am Soc Nephrol Y1 - 2015 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Peralta, Carmen A A1 - Fried, Linda F A1 - Siscovick, David S A1 - Rifkin, Dena E A1 - Hirsch, Calvin A1 - Cummings, Steven R A1 - Harris, Tamara B A1 - Kritchevsky, Stephen B A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Ix, Joachim H KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Continental Population Groups KW - Creatinine KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Male KW - Proportional Hazards Models KW - Regression Analysis KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Sex Factors KW - Smoking KW - Stroke AB -

BACKGROUND 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.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25710804?dopt=Abstract ER - TY - JOUR T1 - Dietary 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. JF - Mol Nutr Food Res Y1 - 2015 A1 - Smith, Caren E A1 - Follis, Jack L A1 - Nettleton, Jennifer A A1 - Foy, Millennia A1 - Wu, Jason H Y A1 - Ma, Yiyi A1 - Tanaka, Toshiko A1 - Manichakul, Ani W A1 - Wu, Hongyu A1 - Chu, Audrey Y A1 - Steffen, Lyn M A1 - Fornage, Myriam A1 - Mozaffarian, Dariush A1 - Kabagambe, Edmond K A1 - Ferruci, Luigi A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - Djoussé, Luc A1 - Ridker, Paul M A1 - Tang, Weihong A1 - McKnight, Barbara A1 - Tsai, Michael Y A1 - Bandinelli, Stefania A1 - Rotter, Jerome I A1 - Hu, Frank B A1 - Chasman, Daniel I A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - King, Irena B A1 - Sun, Qi A1 - Wang, Lu A1 - Lumley, Thomas A1 - Chiuve, Stephanie E A1 - Siscovick, David S A1 - Ordovas, Jose M A1 - Lemaitre, Rozenn N KW - Acetyltransferases KW - Acyltransferases KW - Adaptor Proteins, Signal Transducing KW - Carboxy-Lyases KW - Diet KW - Docosahexaenoic Acids KW - Eicosapentaenoic Acid KW - Erythrocyte Membrane KW - Fatty Acid Desaturases KW - Fatty Acids KW - Fatty Acids, Omega-3 KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

SCOPE: 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.

VL - 59 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25626431?dopt=Abstract ER - TY - JOUR T1 - Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. JF - PLoS One Y1 - 2015 A1 - Bis, Joshua C A1 - Sitlani, Colleen A1 - Irvin, Ryan A1 - Avery, Christy L A1 - Smith, Albert Vernon A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Musani, Solomon K A1 - Li, Xiaohui A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Harris, Tamara B A1 - Quibrera, P Miguel A1 - Brody, Jennifer A A1 - Demissie, Serkalem A1 - Davis, Barry R A1 - Wiggins, Kerri L A1 - Tranah, Gregory J A1 - Lange, Leslie A A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Franco, Oscar H A1 - Launer, Lenore J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Cupples, L Adrienne A1 - Eckfeldt, John H A1 - Smith, Nicholas L A1 - Liu, Yongmei A1 - Wilson, James G A1 - Heckbert, Susan R A1 - Buckley, Brendan M A1 - Ikram, M Arfan A1 - Boerwinkle, Eric A1 - Chen, Yii-Der Ida A1 - de Craen, Anton J M A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Ford, Ian A1 - Hofman, Albert A1 - Sattar, Naveed A1 - Slagboom, P Eline A1 - Westendorp, Rudi G J A1 - Gudnason, Vilmundur A1 - Vasan, Ramachandran S A1 - Lumley, Thomas A1 - Cummings, Steven R A1 - Taylor, Herman A A1 - Post, Wendy A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Whitsel, Eric A A1 - Psaty, Bruce M A1 - Arnett, Donna KW - African Americans KW - Aged KW - Antihypertensive Agents KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Treatment Outcome AB -

BACKGROUND: 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.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract ER - TY - JOUR T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. JF - Nature Y1 - 2015 A1 - Do, Ron A1 - Stitziel, Nathan O A1 - Won, Hong-Hee A1 - Jørgensen, Anders Berg A1 - Duga, Stefano A1 - Angelica Merlini, Pier A1 - Kiezun, Adam A1 - Farrall, Martin A1 - Goel, Anuj A1 - Zuk, Or A1 - Guella, Illaria A1 - Asselta, Rosanna A1 - Lange, Leslie A A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Farlow, Deborah N A1 - DePristo, Mark A A1 - Roberts, Robert A1 - Stewart, Alexander F R A1 - Saleheen, Danish A1 - Danesh, John A1 - Epstein, Stephen E A1 - Sivapalaratnam, Suthesh A1 - Hovingh, G Kees A1 - Kastelein, John J A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Shah, Svati H A1 - Kraus, William E A1 - Davies, Robert A1 - Nikpay, Majid A1 - Johansen, Christopher T A1 - Wang, Jian A1 - Hegele, Robert A A1 - Hechter, Eliana A1 - März, Winfried A1 - Kleber, Marcus E A1 - Huang, Jie A1 - Johnson, Andrew D A1 - Li, Mingyao A1 - Burke, Greg L A1 - Gross, Myron A1 - Liu, Yongmei A1 - Assimes, Themistocles L A1 - Heiss, Gerardo A1 - Lange, Ethan M A1 - Folsom, Aaron R A1 - Taylor, Herman A A1 - Olivieri, Oliviero A1 - Hamsten, Anders A1 - Clarke, Robert A1 - Reilly, Dermot F A1 - Yin, Wu A1 - Rivas, Manuel A A1 - Donnelly, Peter A1 - Rossouw, Jacques E A1 - Psaty, Bruce M A1 - Herrington, David M A1 - Wilson, James G A1 - Rich, Stephen S A1 - Bamshad, Michael J A1 - Tracy, Russell P A1 - Cupples, L Adrienne A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Spertus, John A A1 - Cresci, Sharon A1 - Hartiala, Jaana A1 - Tang, W H Wilson A1 - Hazen, Stanley L A1 - Allayee, Hooman A1 - Reiner, Alex P A1 - Carlson, Christopher S A1 - Kooperberg, Charles A1 - Jackson, Rebecca D A1 - Boerwinkle, Eric A1 - Lander, Eric S A1 - Schwartz, Stephen M A1 - Siscovick, David S A1 - McPherson, Ruth A1 - Tybjaerg-Hansen, Anne A1 - Abecasis, Goncalo R A1 - Watkins, Hugh A1 - Nickerson, Deborah A A1 - Ardissino, Diego A1 - Sunyaev, Shamil R A1 - O'Donnell, Christopher J A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Kathiresan, Sekar KW - Age Factors KW - Age of Onset KW - Alleles KW - Apolipoproteins A KW - Case-Control Studies KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Receptors, LDL KW - Triglycerides KW - United States AB -

Myocardial 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.

VL - 518 IS - 7537 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract ER - TY - JOUR T1 - Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. JF - Hum Mol Genet Y1 - 2015 A1 - Nettleton, Jennifer A A1 - Follis, Jack L A1 - Ngwa, Julius S A1 - Smith, Caren E A1 - Ahmad, Shafqat A1 - Tanaka, Toshiko A1 - Wojczynski, Mary K A1 - Voortman, Trudy A1 - Lemaitre, Rozenn N A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Houston, Denise K A1 - Perälä, Mia-Maria A1 - Qi, Qibin A1 - Sonestedt, Emily A1 - Manichaikul, Ani A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Mikkilä, Vera A1 - North, Kari E A1 - Siscovick, David S A1 - Harald, Kennet A1 - McKeown, Nicola M A1 - Johansson, Ingegerd A1 - Rissanen, Harri A1 - Liu, Yongmei A1 - Lahti, Jari A1 - Hu, Frank B A1 - Bandinelli, Stefania A1 - Rukh, Gull A1 - Rich, Stephen A1 - Booij, Lisanne A1 - Dmitriou, Maria A1 - Ax, Erika A1 - Raitakari, Olli A1 - Mukamal, Kenneth A1 - Männistö, Satu A1 - Hallmans, Göran A1 - Jula, Antti A1 - Ericson, Ulrika A1 - Jacobs, David R A1 - van Rooij, Frank J A A1 - Deloukas, Panos A1 - Sjogren, Per A1 - Kähönen, Mika A1 - Djoussé, Luc A1 - Perola, Markus A1 - Barroso, Inês A1 - Hofman, Albert A1 - Stirrups, Kathleen A1 - Viikari, Jorma A1 - Uitterlinden, André G A1 - Kalafati, Ioanna P A1 - Franco, Oscar H A1 - Mozaffarian, Dariush A1 - Salomaa, Veikko A1 - Borecki, Ingrid B A1 - Knekt, Paul A1 - Kritchevsky, Stephen B A1 - Eriksson, Johan G A1 - Dedoussis, George V A1 - Qi, Lu A1 - Ferrucci, Luigi A1 - Orho-Melander, Marju A1 - Zillikens, M Carola A1 - Ingelsson, Erik A1 - Lehtimäki, Terho A1 - Renstrom, Frida A1 - Cupples, L Adrienne A1 - Loos, Ruth J F A1 - Franks, Paul W KW - Adult KW - Body Mass Index KW - Case-Control Studies KW - Diet, Western KW - Epistasis, Genetic KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity 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.

VL - 24 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25994509?dopt=Abstract ER - TY - JOUR T1 - Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. JF - Am J Hematol Y1 - 2015 A1 - Tang, Weihong A1 - Cushman, Mary A1 - Green, David A1 - Rich, Stephen S A1 - Lange, Leslie A A1 - Yang, Qiong A1 - Tracy, Russell P A1 - Tofler, Geoffrey H A1 - Basu, Saonli A1 - Wilson, James G A1 - Keating, Brendan J A1 - Weng, Lu-Chen A1 - Taylor, Herman A A1 - Jacobs, David R A1 - Delaney, Joseph A A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Pankow, James S A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Reiner, Alexander P A1 - Folsom, Aaron R KW - Adult KW - African Americans KW - Aged KW - European Continental Ancestry Group KW - Factor VIII KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Methionine Adenosyltransferase KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Venous Thromboembolism KW - von Willebrand Factor AB -

Coagulation 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.

VL - 90 IS - 6 ER - TY - JOUR T1 - Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. JF - Diabetes Care Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Garaulet, Marta A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Kiefte-de Jong, Jessica C A1 - Lamon-Fava, Stefania A1 - Scheer, Frank A J L A1 - Bartz, Traci M A1 - Kovanen, Leena A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Ahluwalia, Tarunveer S A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Muka, Taulant A1 - Kalafati, Ioanna P A1 - Mikkilä, Vera A1 - Ordovas, Jose M KW - Adult KW - Alleles KW - Blood Glucose KW - Circadian Rhythm Signaling Peptides and Proteins KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diet, Fat-Restricted KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Gene-Environment Interaction KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Multicenter Studies as Topic KW - Observational Studies as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Sleep KW - Waist Circumference AB -

OBJECTIVE: 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.

VL - 38 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract ER - TY - JOUR T1 - Generalized estimating equations for genome-wide association studies using longitudinal phenotype data. JF - Stat Med Y1 - 2015 A1 - Sitlani, Colleen M A1 - Rice, Kenneth M A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Cupples, L Adrienne A1 - Avery, Christy L A1 - Noordam, Raymond A1 - Stricker, Bruno H C A1 - Whitsel, Eric A A1 - Psaty, Bruce M KW - Aged KW - Aging KW - Cardiovascular Diseases KW - Cohort Studies KW - Computer Simulation KW - Cross-Sectional Studies KW - Epidemiologic Research Design KW - Gene-Environment Interaction KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Meta-Analysis as Topic KW - Models, Genetic KW - Pharmacogenetics KW - Risk Assessment KW - United States AB -

Many 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.

VL - 34 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25297442?dopt=Abstract ER - TY - JOUR T1 - Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. JF - Stroke Y1 - 2015 A1 - Lopez, Lorna M A1 - Hill, W David A1 - Harris, Sarah E A1 - Valdes Hernandez, Maria A1 - Munoz Maniega, Susana A1 - Bastin, Mark E A1 - Bailey, Emma A1 - Smith, Colin A1 - McBride, Martin A1 - McClure, John A1 - Graham, Delyth A1 - Dominiczak, Anna A1 - Yang, Qiong A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Launer, Lenore A1 - Bis, Joshua C A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Porteous, David J A1 - Starr, John A1 - Deary, Ian J A1 - Wardlaw, Joanna M KW - Aged KW - Alzheimer Disease KW - Animals KW - Brain KW - Causality KW - Dementia KW - Female KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Polymorphism, Single Nucleotide KW - Rats KW - Rats, Inbred SHR KW - Rats, Wistar KW - Risk Factors KW - Translational Medical Research KW - White Matter AB -

BACKGROUND 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.

VL - 46 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25586835?dopt=Abstract ER - TY - JOUR T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). JF - Mol Psychiatry Y1 - 2015 A1 - Davies, G A1 - Armstrong, N A1 - Bis, J C A1 - Bressler, J A1 - Chouraki, V A1 - Giddaluru, S A1 - Hofer, E A1 - Ibrahim-Verbaas, C A A1 - Kirin, M A1 - Lahti, J A1 - van der Lee, S J A1 - Le Hellard, S A1 - Liu, T A1 - Marioni, R E A1 - Oldmeadow, C A1 - Postmus, I A1 - Smith, A V A1 - Smith, J A A1 - Thalamuthu, A A1 - Thomson, R A1 - Vitart, V A1 - Wang, J A1 - Yu, L A1 - Zgaga, L A1 - Zhao, W A1 - Boxall, R A1 - Harris, S E A1 - Hill, W D A1 - Liewald, D C A1 - Luciano, M A1 - Adams, H A1 - Ames, D A1 - Amin, N A1 - Amouyel, P A1 - Assareh, A A A1 - Au, R A1 - Becker, J T A1 - Beiser, A A1 - Berr, C A1 - Bertram, L A1 - Boerwinkle, E A1 - Buckley, B M A1 - Campbell, H A1 - Corley, J A1 - De Jager, P L A1 - Dufouil, C A1 - Eriksson, J G A1 - Espeseth, T A1 - Faul, J D A1 - Ford, I A1 - Gottesman, R F A1 - Griswold, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heiss, G A1 - Hofman, A A1 - Holliday, E G A1 - Huffman, J A1 - Kardia, S L R A1 - Kochan, N A1 - Knopman, D S A1 - Kwok, J B A1 - Lambert, J-C A1 - Lee, T A1 - Li, G A1 - Li, S-C A1 - Loitfelder, M A1 - Lopez, O L A1 - Lundervold, A J A1 - Lundqvist, A A1 - Mather, K A A1 - Mirza, S S A1 - Nyberg, L A1 - Oostra, B A A1 - Palotie, A A1 - Papenberg, G A1 - Pattie, A A1 - Petrovic, K A1 - Polasek, O A1 - Psaty, B M A1 - Redmond, P A1 - Reppermund, S A1 - Rotter, J I A1 - Schmidt, H A1 - Schuur, M A1 - Schofield, P W A1 - Scott, R J A1 - Steen, V M A1 - Stott, D J A1 - van Swieten, J C A1 - Taylor, K D A1 - Trollor, J A1 - Trompet, S A1 - Uitterlinden, A G A1 - Weinstein, G A1 - Widen, E A1 - Windham, B G A1 - Jukema, J W A1 - Wright, A F A1 - Wright, M J A1 - Yang, Q A1 - Amieva, H A1 - Attia, J R A1 - Bennett, D A A1 - Brodaty, H A1 - de Craen, A J M A1 - Hayward, C A1 - Ikram, M A A1 - Lindenberger, U A1 - Nilsson, L-G A1 - Porteous, D J A1 - Räikkönen, K A1 - Reinvang, I A1 - Rudan, I A1 - Sachdev, P S A1 - Schmidt, R A1 - Schofield, P R A1 - Srikanth, V A1 - Starr, J M A1 - Turner, S T A1 - Weir, D R A1 - Wilson, J F A1 - van Duijn, C A1 - Launer, L A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - Mosley, T H A1 - Deary, I J KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cognition KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - HMGN1 Protein KW - Humans KW - Male KW - Middle Aged KW - Neuropsychological Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Scotland AB -

General 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.

VL - 20 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract ER - TY - JOUR T1 - Genetic loci associated with circulating levels of very long-chain saturated fatty acids. JF - J Lipid Res Y1 - 2015 A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Kabagambe, Edmond K A1 - Wu, Jason H Y A1 - McKnight, Barbara A1 - Manichaikul, Ani A1 - Guan, Weihua A1 - Sun, Qi A1 - Chasman, Daniel I A1 - Foy, Millennia A1 - Wang, Lu A1 - Zhu, Jingwen A1 - Siscovick, David S A1 - Tsai, Michael Y A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Djoussé, Luc A1 - Chen, Yii-der I A1 - Tang, Weihong A1 - Weng, Lu-Chen A1 - Wu, Hongyu A1 - Jensen, Majken K A1 - Chu, Audrey Y A1 - Jacobs, David R A1 - Rich, Stephen S A1 - Mozaffarian, Dariush A1 - Steffen, Lyn A1 - Rimm, Eric B A1 - Hu, Frank B A1 - Ridker, Paul M A1 - Fornage, Myriam A1 - Friedlander, Yechiel KW - Cohort Studies KW - Fatty Acids KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans AB -

Very 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.

VL - 56 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25378659?dopt=Abstract ER - TY - JOUR T1 - Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. JF - Am J Clin Nutr Y1 - 2015 A1 - Mozaffarian, Dariush A1 - Kabagambe, Edmond K A1 - Johnson, Catherine O A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - Sun, Qi A1 - Foy, Millennia A1 - Wang, Lu A1 - Wiener, Howard A1 - Irvin, Marguerite R A1 - Rich, Stephen S A1 - Wu, Hongyu A1 - Jensen, Majken K A1 - Chasman, Daniel I A1 - Chu, Audrey Y A1 - Fornage, Myriam A1 - Steffen, Lyn A1 - King, Irena B A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Djoussé, Luc A1 - Chen, Ida Y-D A1 - Wu, Jason H Y A1 - Siscovick, David S A1 - Ridker, Paul M A1 - Tsai, Michael Y A1 - Rimm, Eric B A1 - Hu, Frank B A1 - Arnett, Donna K KW - African Americans KW - Arachidonic Acid KW - Asian Americans KW - Biomarkers KW - European Continental Ancestry Group KW - Fatty Acids, Omega-6 KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Loci KW - Genotyping Techniques KW - Humans KW - Phospholipids KW - Polymorphism, Single Nucleotide KW - Trans Fatty Acids AB -

BACKGROUND: 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.

VL - 101 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25646338?dopt=Abstract ER - TY - JOUR T1 - Genetic overlap between diagnostic subtypes of ischemic stroke. JF - Stroke Y1 - 2015 A1 - Holliday, Elizabeth G A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Bevan, Steve A1 - Falcone, Guido A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Cotlarciuc, Ioana A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Boncoraglio, Giorgio B A1 - Clarke, Robert A1 - Cole, John W A1 - Fornage, Myriam A1 - Furie, Karen L A1 - Ikram, M Arfan A1 - Jannes, Jim A1 - Kittner, Steven J A1 - Lincz, Lisa F A1 - Maguire, Jane M A1 - Meschia, James F A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Oldmeadow, Christopher A1 - Parati, Eugenio A A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Seshadri, Sudha A1 - Scott, Rodney J A1 - Sharma, Pankaj A1 - Sudlow, Cathie A1 - Wiggins, Kerri L A1 - Worrall, Bradford B A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Levi, Christopher A1 - Attia, John A1 - Wray, Naomi R KW - Alleles KW - Atherosclerosis KW - Cerebral Small Vessel Diseases KW - Cohort Studies KW - Data Interpretation, Statistical KW - Embolism KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Ischemia KW - Linear Models KW - Meta-Analysis as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Stroke AB -

BACKGROUND 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.

VL - 46 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract ER - TY - JOUR T1 - Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. JF - Nat Commun Y1 - 2015 A1 - van Leeuwen, Elisabeth M A1 - Karssen, Lennart C A1 - Deelen, Joris A1 - Isaacs, Aaron A1 - Medina-Gómez, Carolina A1 - Mbarek, Hamdi A1 - Kanterakis, Alexandros A1 - Trompet, Stella A1 - Postmus, Iris A1 - Verweij, Niek A1 - van Enckevort, David J A1 - Huffman, Jennifer E A1 - White, Charles C A1 - Feitosa, Mary F A1 - Bartz, Traci M A1 - Manichaikul, Ani A1 - Joshi, Peter K A1 - Peloso, Gina M A1 - Deelen, Patrick A1 - van Dijk, Freerk A1 - Willemsen, Gonneke A1 - de Geus, Eco J A1 - Milaneschi, Yuri A1 - Penninx, Brenda W J H A1 - Francioli, Laurent C A1 - Menelaou, Androniki A1 - Pulit, Sara L A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Franco, Oscar H A1 - Mateo Leach, Irene A1 - Beekman, Marian A1 - de Craen, Anton J M A1 - Uh, Hae-Won A1 - Trochet, Holly A1 - Hocking, Lynne J A1 - Porteous, David J A1 - Sattar, Naveed A1 - Packard, Chris J A1 - Buckley, Brendan M A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Rotter, Jerome I A1 - Mychaleckyj, Josyf C A1 - Campbell, Harry A1 - Duan, Qing A1 - Lange, Leslie A A1 - Wilson, James F A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Rudan, Igor A1 - Wright, Alan F A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Kearney, Patricia M A1 - Stott, David J A1 - Adrienne Cupples, L A1 - Jukema, J Wouter A1 - van der Harst, Pim A1 - Sijbrands, Eric J A1 - Hottenga, Jouke-Jan A1 - Uitterlinden, André G A1 - Swertz, Morris A A1 - van Ommen, Gert-Jan B A1 - de Bakker, Paul I W A1 - Eline Slagboom, P A1 - Boomsma, Dorret I A1 - Wijmenga, Cisca A1 - van Duijn, Cornelia M KW - ATP-Binding Cassette Transporters KW - Cholesterol KW - Gene Frequency KW - Genetic Association Studies KW - Humans KW - Mutation, Missense KW - Netherlands AB -

Variants 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.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25751400?dopt=Abstract ER - TY - JOUR T1 - Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Minster, Ryan L A1 - Sanders, Jason L A1 - Singh, Jatinder A1 - Kammerer, Candace M A1 - Barmada, M Michael A1 - Matteini, Amy M A1 - Zhang, Qunyuan A1 - Wojczynski, Mary K A1 - Daw, E Warwick A1 - Brody, Jennifer A A1 - Arnold, Alice M A1 - Lunetta, Kathryn L A1 - Murabito, Joanne M A1 - Christensen, Kaare A1 - Perls, Thomas T A1 - Province, Michael A A1 - Newman, Anne B KW - Aging KW - Apolipoproteins E KW - Forkhead Transcription Factors KW - Genetic Linkage KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

BACKGROUND: 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.

VL - 70 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25758594?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. JF - Mol Psychiatry Y1 - 2015 A1 - Cornelis, M C A1 - Byrne, E M A1 - Esko, T A1 - Nalls, M A A1 - Ganna, A A1 - Paynter, N A1 - Monda, K L A1 - Amin, N A1 - Fischer, K A1 - Renstrom, F A1 - Ngwa, J S A1 - Huikari, V A1 - Cavadino, A A1 - Nolte, I M A1 - Teumer, A A1 - Yu, K A1 - Marques-Vidal, P A1 - Rawal, R A1 - Manichaikul, A A1 - Wojczynski, M K A1 - Vink, J M A1 - Zhao, J H A1 - Burlutsky, G A1 - Lahti, J A1 - Mikkilä, V A1 - Lemaitre, R N A1 - Eriksson, J A1 - Musani, S K A1 - Tanaka, T A1 - Geller, F A1 - Luan, J A1 - Hui, J A1 - Mägi, R A1 - Dimitriou, M A1 - Garcia, M E A1 - Ho, W-K A1 - Wright, M J A1 - Rose, L M A1 - Magnusson, P K E A1 - Pedersen, N L A1 - Couper, D A1 - Oostra, B A A1 - Hofman, A A1 - Ikram, M A A1 - Tiemeier, H W A1 - Uitterlinden, A G A1 - van Rooij, F J A A1 - Barroso, I A1 - Johansson, I A1 - Xue, L A1 - Kaakinen, M A1 - Milani, L A1 - Power, C A1 - Snieder, H A1 - Stolk, R P A1 - Baumeister, S E A1 - Biffar, R A1 - Gu, F A1 - Bastardot, F A1 - Kutalik, Z A1 - Jacobs, D R A1 - Forouhi, N G A1 - Mihailov, E A1 - Lind, L A1 - Lindgren, C A1 - Michaëlsson, K A1 - Morris, A A1 - Jensen, M A1 - Khaw, K-T A1 - Luben, R N A1 - Wang, J J A1 - Männistö, S A1 - Perälä, M-M A1 - Kähönen, M A1 - Lehtimäki, T A1 - Viikari, J A1 - Mozaffarian, D A1 - Mukamal, K A1 - Psaty, B M A1 - Döring, A A1 - Heath, A C A1 - Montgomery, G W A1 - Dahmen, N A1 - Carithers, T A1 - Tucker, K L A1 - Ferrucci, L A1 - Boyd, H A A1 - Melbye, M A1 - Treur, J L A1 - Mellström, D A1 - Hottenga, J J A1 - Prokopenko, I A1 - Tönjes, A A1 - Deloukas, P A1 - Kanoni, S A1 - Lorentzon, M A1 - Houston, D K A1 - Liu, Y A1 - Danesh, J A1 - Rasheed, A A1 - Mason, M A A1 - Zonderman, A B A1 - Franke, L A1 - Kristal, B S A1 - Karjalainen, J A1 - Reed, D R A1 - Westra, H-J A1 - Evans, M K A1 - Saleheen, D A1 - Harris, T B A1 - Dedoussis, G A1 - Curhan, G A1 - Stumvoll, M A1 - Beilby, J A1 - Pasquale, L R A1 - Feenstra, B A1 - Bandinelli, S A1 - Ordovás, J M A1 - Chan, A T A1 - Peters, U A1 - Ohlsson, C A1 - Gieger, C A1 - Martin, N G A1 - Waldenberger, M A1 - Siscovick, D S A1 - Raitakari, O A1 - Eriksson, J G A1 - Mitchell, P A1 - Hunter, D J A1 - Kraft, P A1 - Rimm, E B A1 - Boomsma, D I A1 - Borecki, I B A1 - Loos, R J F A1 - Wareham, N J A1 - Vollenweider, P A1 - Caporaso, N A1 - Grabe, H J A1 - Neuhouser, M L A1 - Wolffenbuttel, B H R A1 - Hu, F B A1 - Hypponen, E A1 - Järvelin, M-R A1 - Cupples, L A A1 - Franks, P W A1 - Ridker, P M A1 - van Duijn, C M A1 - Heiss, G A1 - Metspalu, A A1 - North, K E A1 - Ingelsson, E A1 - Nettleton, J A A1 - van Dam, R M A1 - Chasman, D I KW - Adaptor Proteins, Signal Transducing KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors KW - Brain-Derived Neurotrophic Factor KW - Coffea KW - Cytochrome P-450 CYP1A2 KW - Food Habits KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Coffee, 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.

VL - 20 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25288136?dopt=Abstract ER - TY - JOUR T1 - Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Biol Psychiatry Y1 - 2015 A1 - Debette, Stephanie A1 - Ibrahim Verbaas, Carla A A1 - Bressler, Jan A1 - Schuur, Maaike A1 - Smith, Albert A1 - Bis, Joshua C A1 - Davies, Gail A1 - Wolf, Christiane A1 - Gudnason, Vilmundur A1 - Chibnik, Lori B A1 - Yang, Qiong A1 - DeStefano, Anita L A1 - de Quervain, Dominique J F A1 - Srikanth, Velandai A1 - Lahti, Jari A1 - Grabe, Hans J A1 - Smith, Jennifer A A1 - Priebe, Lutz A1 - Yu, Lei A1 - Karbalai, Nazanin A1 - Hayward, Caroline A1 - Wilson, James F A1 - Campbell, Harry A1 - Petrovic, Katja A1 - Fornage, Myriam A1 - Chauhan, Ganesh A1 - Yeo, Robin A1 - Boxall, Ruth A1 - Becker, James A1 - Stegle, Oliver A1 - Mather, Karen A A1 - Chouraki, Vincent A1 - Sun, Qi A1 - Rose, Lynda M A1 - Resnick, Susan A1 - Oldmeadow, Christopher A1 - Kirin, Mirna A1 - Wright, Alan F A1 - Jonsdottir, Maria K A1 - Au, Rhoda A1 - Becker, Albert A1 - Amin, Najaf A1 - Nalls, Mike A A1 - Turner, Stephen T A1 - Kardia, Sharon L R A1 - Oostra, Ben A1 - Windham, Gwen A1 - Coker, Laura H A1 - Zhao, Wei A1 - Knopman, David S A1 - Heiss, Gerardo A1 - Griswold, Michael E A1 - Gottesman, Rebecca F A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Zgaga, Lina A1 - Rudan, Igor A1 - Polasek, Ozren A1 - Holliday, Elizabeth G A1 - Schofield, Peter A1 - Choi, Seung Hoan A1 - Tanaka, Toshiko A1 - An, Yang A1 - Perry, Rodney T A1 - Kennedy, Richard E A1 - Sale, Michèle M A1 - Wang, Jing A1 - Wadley, Virginia G A1 - Liewald, David C A1 - Ridker, Paul M A1 - Gow, Alan J A1 - Pattie, Alison A1 - Starr, John M A1 - Porteous, David A1 - Liu, Xuan A1 - Thomson, Russell A1 - Armstrong, Nicola J A1 - Eiriksdottir, Gudny A1 - Assareh, Arezoo A A1 - Kochan, Nicole A A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Hsieh, Yi-Chen A1 - Eriksson, Johan G A1 - Vogler, Christian A1 - van Swieten, John C A1 - Shulman, Joshua M A1 - Beiser, Alexa A1 - Rotter, Jerome A1 - Schmidt, Carsten O A1 - Hoffmann, Wolfgang A1 - Nöthen, Markus M A1 - Ferrucci, Luigi A1 - Attia, John A1 - Uitterlinden, André G A1 - Amouyel, Philippe A1 - Dartigues, Jean-François A1 - Amieva, Hélène A1 - Räikkönen, Katri A1 - Garcia, Melissa A1 - Wolf, Philip A A1 - Hofman, Albert A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - DeJager, Philip L A1 - Sachdev, Perminder S A1 - Schmidt, Reinhold A1 - Breteler, Monique M B A1 - Teumer, Alexander A1 - Lopez, Oscar L A1 - Cichon, Sven A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Müller-Myhsok, Bertram A1 - Tzourio, Christophe A1 - Papassotiropoulos, Andreas A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Mosley, Thomas H KW - Aged KW - Aged, 80 and over KW - Aging KW - Apolipoproteins E KW - Claudin-5 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Memory Disorders KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proteins KW - Proteoglycans KW - Regression Analysis KW - Sulfotransferases KW - Verbal Learning AB -

BACKGROUND: 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.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Broer, Linda A1 - Buchman, Aron S A1 - Deelen, Joris A1 - Evans, Daniel S A1 - Faul, Jessica D A1 - Lunetta, Kathryn L A1 - Sebastiani, Paola A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Tanaka, Toshiko A1 - Yu, Lei A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Benjamin, Emelia J A1 - De Jager, Philip L A1 - Eirkisdottir, Gudny A1 - Evans, Denis A A1 - Garcia, Melissa E A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kiel, Douglas P A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Singleton, Andrew A1 - Tiemeier, Henning A1 - Uitterlinden, André G A1 - Zhao, Wei A1 - Bandinelli, Stefania A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Karasik, David A1 - Launer, Lenore J A1 - Perls, Thomas T A1 - Slagboom, P Eline A1 - Tranah, Gregory J A1 - Weir, David R A1 - Newman, Anne B A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid AB -

BACKGROUND: 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.

VL - 70 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract ER - TY - JOUR T1 - Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. JF - Am J Clin Nutr Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Lamon-Fava, Stefania A1 - Richardson, Kris A1 - Saxena, Richa A1 - Scheer, Frank A J L A1 - Kovanen, Leena A1 - Bartz, Traci M A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Frazier-Wood, Alexis C A1 - Kalafati, Ioanna-Panagiota A1 - Mikkilä, Vera A1 - Partonen, Timo A1 - Lemaitre, Rozenn N A1 - Lahti, Jari A1 - Hernandez, Dena G A1 - Toft, Ulla A1 - Johnson, W Craig A1 - Kanoni, Stavroula A1 - Raitakari, Olli T A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Grarup, Niels A1 - Highland, Heather M A1 - Rallidis, Loukianos A1 - Kähönen, Mika A1 - Havulinna, Aki S A1 - Siscovick, David S A1 - Räikkönen, Katri A1 - Jørgensen, Torben A1 - Rotter, Jerome I A1 - Deloukas, Panos A1 - Viikari, Jorma S A A1 - Mozaffarian, Dariush A1 - Linneberg, Allan A1 - Seppälä, Ilkka A1 - Hansen, Torben A1 - Salomaa, Veikko A1 - Gharib, Sina A A1 - Eriksson, Johan G A1 - Bandinelli, Stefania A1 - Pedersen, Oluf A1 - Rich, Stephen S A1 - Dedoussis, George A1 - Lehtimäki, Terho A1 - Ordovas, Jose M KW - Adult KW - Body Mass Index KW - CLOCK Proteins KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fatty Acids, Unsaturated KW - Female KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Sleep KW - Young Adult AB -

BACKGROUND: 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.

VL - 101 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25527757?dopt=Abstract ER - TY - JOUR T1 - Higher circulating adiponectin levels are associated with increased risk of atrial fibrillation in older adults. JF - Heart Y1 - 2015 A1 - Macheret, Fima A1 - Bartz, Traci M A1 - Djoussé, Luc A1 - Ix, Joachim H A1 - Mukamal, Kenneth J A1 - Zieman, Susan J A1 - Siscovick, David S A1 - Tracy, Russell P A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Kizer, Jorge R KW - Adiponectin KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Atrial Fibrillation KW - Biomarkers KW - Female KW - Humans KW - Incidence KW - Linear Models KW - Male KW - Multivariate Analysis KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States KW - Up-Regulation AB -

BACKGROUND: 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.

VL - 101 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25855796?dopt=Abstract ER - TY - JOUR T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. JF - Lancet Y1 - 2015 A1 - Swerdlow, Daniel I A1 - Preiss, David A1 - Kuchenbaecker, Karoline B A1 - Holmes, Michael V A1 - Engmann, Jorgen E L A1 - Shah, Tina A1 - Sofat, Reecha A1 - Stender, Stefan A1 - Johnson, Paul C D A1 - Scott, Robert A A1 - Leusink, Maarten A1 - Verweij, Niek A1 - Sharp, Stephen J A1 - Guo, Yiran A1 - Giambartolomei, Claudia A1 - Chung, Christina A1 - Peasey, Anne A1 - Amuzu, Antoinette A1 - Li, KaWah A1 - Palmen, Jutta A1 - Howard, Philip A1 - Cooper, Jackie A A1 - Drenos, Fotios A1 - Li, Yun R A1 - Lowe, Gordon A1 - Gallacher, John A1 - Stewart, Marlene C W A1 - Tzoulaki, Ioanna A1 - Buxbaum, Sarah G A1 - van der A, Daphne L A1 - Forouhi, Nita G A1 - Onland-Moret, N Charlotte A1 - van der Schouw, Yvonne T A1 - Schnabel, Renate B A1 - Hubacek, Jaroslav A A1 - Kubinova, Ruzena A1 - Baceviciene, Migle A1 - Tamosiunas, Abdonas A1 - Pajak, Andrzej A1 - Topor-Madry, Roman A1 - Stepaniak, Urszula A1 - Malyutina, Sofia A1 - Baldassarre, Damiano A1 - Sennblad, Bengt A1 - Tremoli, Elena A1 - de Faire, Ulf A1 - Veglia, Fabrizio A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Westendorp, Rudi G J A1 - de Borst, Gert Jan A1 - de Jong, Pim A A1 - Algra, Ale A1 - Spiering, Wilko A1 - Maitland-van der Zee, Anke H A1 - Klungel, Olaf H A1 - de Boer, Anthonius A1 - Doevendans, Pieter A A1 - Eaton, Charles B A1 - Robinson, Jennifer G A1 - Duggan, David A1 - Kjekshus, John A1 - Downs, John R A1 - Gotto, Antonio M A1 - Keech, Anthony C A1 - Marchioli, Roberto A1 - Tognoni, Gianni A1 - Sever, Peter S A1 - Poulter, Neil R A1 - Waters, David D A1 - Pedersen, Terje R A1 - Amarenco, Pierre A1 - Nakamura, Haruo A1 - McMurray, John J V A1 - Lewsey, James D A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Maggioni, Aldo P A1 - Tavazzi, Luigi A1 - Ray, Kausik K A1 - Seshasai, Sreenivasa Rao Kondapally A1 - Manson, JoAnn E A1 - Price, Jackie F A1 - Whincup, Peter H A1 - Morris, Richard W A1 - Lawlor, Debbie A A1 - Smith, George Davey A1 - Ben-Shlomo, Yoav A1 - Schreiner, Pamela J A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Cushman, Mary A1 - Kumari, Meena A1 - Wareham, Nick J A1 - Verschuren, W M Monique A1 - Redline, Susan A1 - Patel, Sanjay R A1 - Whittaker, John C A1 - Hamsten, Anders A1 - Delaney, Joseph A A1 - Dale, Caroline A1 - Gaunt, Tom R A1 - Wong, Andrew A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Kathiresan, Sekar A1 - Castillo, Berta A A1 - van der Harst, Pim A1 - Brunner, Eric J A1 - Tybjaerg-Hansen, Anne A1 - Marmot, Michael G A1 - Krauss, Ronald M A1 - Tsai, Michael A1 - Coresh, Josef A1 - Hoogeveen, Ronald C A1 - Psaty, Bruce M A1 - Lange, Leslie A A1 - Hakonarson, Hakon A1 - Dudbridge, Frank A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Timpson, Nicholas J A1 - Langenberg, Claudia A1 - Asselbergs, Folkert W A1 - Voevoda, Mikhail A1 - Bobak, Martin A1 - Pikhart, Hynek A1 - Wilson, James G A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Sattar, Naveed KW - Aged KW - Body Mass Index KW - Body Weight KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Testing KW - Humans KW - Hydroxymethylglutaryl CoA Reductases KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Randomized Controlled Trials as Topic KW - Risk Factors AB -

BACKGROUND: 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.

VL - 385 IS - 9965 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract ER - TY - JOUR T1 - Integrative pathway genomics of lung function and airflow obstruction. JF - Hum Mol Genet Y1 - 2015 A1 - Gharib, Sina A A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Birkland, Timothy P A1 - Wilk, Jemma B A1 - Wain, Louise V A1 - Brody, Jennifer A A1 - Obeidat, Ma'en A1 - Hancock, Dana B A1 - Tang, Wenbo A1 - Rawal, Rajesh A1 - Boezen, H Marike A1 - Imboden, Medea A1 - Huffman, Jennifer E A1 - Lahousse, Lies A1 - Alves, Alexessander C A1 - Manichaikul, Ani A1 - Hui, Jennie A1 - Morrison, Alanna C A1 - Ramasamy, Adaikalavan A1 - Smith, Albert Vernon A1 - Gudnason, Vilmundur A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Evans, David M A1 - Strachan, David P A1 - Deary, Ian J A1 - Hofman, Albert A1 - Gläser, Sven A1 - Wilson, James F A1 - North, Kari E A1 - Zhao, Jing Hua A1 - Heckbert, Susan R A1 - Jarvis, Deborah L A1 - Probst-Hensch, Nicole A1 - Schulz, Holger A1 - Barr, R Graham A1 - Jarvelin, Marjo-Riitta A1 - O'Connor, George T A1 - Kähönen, Mika A1 - Cassano, Patricia A A1 - Hysi, Pirro G A1 - Dupuis, Josée A1 - Hayward, Caroline A1 - Psaty, Bruce M A1 - Hall, Ian P A1 - Parks, William C A1 - Tobin, Martin D A1 - London, Stephanie J KW - Airway Obstruction KW - Animals KW - Cell Proliferation KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Immune System KW - Lung KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Signal Transduction AB -

Chronic 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.

VL - 24 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26395457?dopt=Abstract ER - TY - JOUR T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. JF - Nat Commun Y1 - 2015 A1 - Wessel, Jennifer A1 - Chu, Audrey Y A1 - Willems, Sara M A1 - Wang, Shuai A1 - Yaghootkar, Hanieh A1 - Brody, Jennifer A A1 - Dauriz, Marco A1 - Hivert, Marie-France A1 - Raghavan, Sridharan A1 - Lipovich, Leonard A1 - Hidalgo, Bertha A1 - Fox, Keolu A1 - Huffman, Jennifer E A1 - An, Ping A1 - Lu, Yingchang A1 - Rasmussen-Torvik, Laura J A1 - Grarup, Niels A1 - Ehm, Margaret G A1 - Li, Li A1 - Baldridge, Abigail S A1 - Stančáková, Alena A1 - Abrol, Ravinder A1 - Besse, Céline A1 - Boland, Anne A1 - Bork-Jensen, Jette A1 - Fornage, Myriam A1 - Freitag, Daniel F A1 - Garcia, Melissa E A1 - Guo, Xiuqing A1 - Hara, Kazuo A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Lange, Leslie A A1 - Layton, Jill C A1 - Li, Man A1 - Hua Zhao, Jing A1 - Meidtner, Karina A1 - Morrison, Alanna C A1 - Nalls, Mike A A1 - Peters, Marjolein J A1 - Sabater-Lleal, Maria A1 - Schurmann, Claudia A1 - Silveira, Angela A1 - Smith, Albert V A1 - Southam, Lorraine A1 - Stoiber, Marcus H A1 - Strawbridge, Rona J A1 - Taylor, Kent D A1 - Varga, Tibor V A1 - Allin, Kristine H A1 - Amin, Najaf A1 - Aponte, Jennifer L A1 - Aung, Tin A1 - Barbieri, Caterina A1 - Bihlmeyer, Nathan A A1 - Boehnke, Michael A1 - Bombieri, Cristina A1 - Bowden, Donald W A1 - Burns, Sean M A1 - Chen, Yuning A1 - Chen, Yii-DerI A1 - Cheng, Ching-Yu A1 - Correa, Adolfo A1 - Czajkowski, Jacek A1 - Dehghan, Abbas A1 - Ehret, Georg B A1 - Eiriksdottir, Gudny A1 - Escher, Stefan A A1 - Farmaki, Aliki-Eleni A1 - Frånberg, Mattias A1 - Gambaro, Giovanni A1 - Giulianini, Franco A1 - Goddard, William A A1 - Goel, Anuj A1 - Gottesman, Omri A1 - Grove, Megan L A1 - Gustafsson, Stefan A1 - Hai, Yang A1 - Hallmans, Göran A1 - Heo, Jiyoung A1 - Hoffmann, Per A1 - Ikram, Mohammad K A1 - Jensen, Richard A A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Karaleftheri, Maria A1 - Khor, Chiea C A1 - Kirkpatrick, Andrea A1 - Kraja, Aldi T A1 - Kuusisto, Johanna A1 - Lange, Ethan M A1 - Lee, I T A1 - Lee, Wen-Jane A1 - Leong, Aaron A1 - Liao, Jiemin A1 - Liu, Chunyu A1 - Liu, Yongmei A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Malerba, Giovanni A1 - Mamakou, Vasiliki A1 - Marouli, Eirini A1 - Maruthur, Nisa M A1 - Matchan, Angela A1 - McKean-Cowdin, Roberta A1 - McLeod, Olga A1 - Metcalf, Ginger A A1 - Mohlke, Karen L A1 - Muzny, Donna M A1 - Ntalla, Ioanna A1 - Palmer, Nicholette D A1 - Pasko, Dorota A1 - Peter, Andreas A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rice, Ken A1 - Sala, Cinzia F A1 - Sennblad, Bengt A1 - Serafetinidis, Ioannis A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Speliotes, Elizabeth K A1 - Stahl, Eli A A1 - Stirrups, Kathleen A1 - Tentolouris, Nikos A1 - Thanopoulou, Anastasia A1 - Torres, Mina A1 - Traglia, Michela A1 - Tsafantakis, Emmanouil A1 - Javad, Sundas A1 - Yanek, Lisa R A1 - Zengini, Eleni A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Brown, James B A1 - Cupples, L Adrienne A1 - Hansen, Torben A1 - Ingelsson, Erik A1 - Karter, Andrew J A1 - Lorenzo, Carlos A1 - Mathias, Rasika A A1 - Norris, Jill M A1 - Peloso, Gina M A1 - Sheu, Wayne H-H A1 - Toniolo, Daniela A1 - Vaidya, Dhananjay A1 - Varma, Rohit A1 - Wagenknecht, Lynne E A1 - Boeing, Heiner A1 - Bottinger, Erwin P A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Ferrannini, Ele A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Gibbs, Richard A A1 - Gudnason, Vilmundur A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Jansson, Jan-Håkan A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Padmanabhan, Sandosh A1 - Pankow, James S A1 - Polasek, Ozren A1 - Province, Michael A A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rudan, Igor A1 - Schulze, Matthias B A1 - Smith, Blair H A1 - Uitterlinden, André G A1 - Walker, Mark A1 - Watkins, Hugh A1 - Wong, Tien Y A1 - Zeggini, Eleftheria A1 - Laakso, Markku A1 - Borecki, Ingrid B A1 - Chasman, Daniel I A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Tai, E Shyong A1 - van Duijn, Cornelia M A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Boerwinkle, Eric A1 - Kao, W H Linda A1 - Florez, Jose C A1 - Loos, Ruth J F A1 - Wilson, James G A1 - Frayling, Timothy M A1 - Siscovick, David S A1 - Dupuis, Josée A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Scott, Robert A A1 - Goodarzi, Mark O KW - African Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Exome KW - Fasting KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glucagon-Like Peptide-1 Receptor KW - Glucose-6-Phosphatase KW - Humans KW - Insulin KW - Mutation Rate KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide AB -

Fasting 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.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract ER - TY - JOUR T1 - Mendelian randomization of blood lipids for coronary heart disease. JF - Eur Heart J Y1 - 2015 A1 - Holmes, Michael V A1 - Asselbergs, Folkert W A1 - Palmer, Tom M A1 - Drenos, Fotios A1 - Lanktree, Matthew B A1 - Nelson, Christopher P A1 - Dale, Caroline E A1 - Padmanabhan, Sandosh A1 - Finan, Chris A1 - Swerdlow, Daniel I A1 - Tragante, Vinicius A1 - van Iperen, Erik P A A1 - Sivapalaratnam, Suthesh A1 - Shah, Sonia A1 - Elbers, Clara C A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Giambartolomei, Claudia A1 - White, Jon A1 - Zabaneh, Delilah A1 - Sofat, Reecha A1 - McLachlan, Stela A1 - Doevendans, Pieter A A1 - Balmforth, Anthony J A1 - Hall, Alistair S A1 - North, Kari E A1 - Almoguera, Berta A1 - Hoogeveen, Ron C A1 - Cushman, Mary A1 - Fornage, Myriam A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Siscovick, David S A1 - Tsai, Michael Y A1 - Karczewski, Konrad J A1 - Hofker, Marten H A1 - Verschuren, W Monique A1 - Bots, Michiel L A1 - van der Schouw, Yvonne T A1 - Melander, Olle A1 - Dominiczak, Anna F A1 - Morris, Richard A1 - Ben-Shlomo, Yoav A1 - Price, Jackie A1 - Kumari, Meena A1 - Baumert, Jens A1 - Peters, Annette A1 - Thorand, Barbara A1 - Koenig, Wolfgang A1 - Gaunt, Tom R A1 - Humphries, Steve E A1 - Clarke, Robert A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Wilson, James G A1 - Rich, Stephen S A1 - de Bakker, Paul I W A1 - Lange, Leslie A A1 - Davey Smith, George A1 - Reiner, Alex P A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Lawlor, Debbie A A1 - Dudbridge, Frank A1 - Samani, Nilesh J A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Casas, Juan P KW - Case-Control Studies KW - Cholesterol, HDL KW - Coronary Artery Disease KW - Female KW - Gene Frequency KW - Genotype KW - Genotyping Techniques KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Triglycerides AB -

AIMS: 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.

VL - 36 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24474739?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. JF - Am J Hum Genet Y1 - 2015 A1 - Germain, Marine A1 - Chasman, Daniel I A1 - de Haan, Hugoline A1 - Tang, Weihong A1 - Lindström, Sara A1 - Weng, Lu-Chen A1 - de Andrade, Mariza A1 - de Visser, Marieke C H A1 - Wiggins, Kerri L A1 - Suchon, Pierre A1 - Saut, Noémie A1 - Smadja, David M A1 - Le Gal, Grégoire A1 - van Hylckama Vlieg, Astrid A1 - Di Narzo, Antonio A1 - Hao, Ke A1 - Nelson, Christopher P A1 - Rocanin-Arjo, Ares A1 - Folkersen, Lasse A1 - Monajemi, Ramin A1 - Rose, Lynda M A1 - Brody, Jennifer A A1 - Slagboom, Eline A1 - Aïssi, Dylan A1 - Gagnon, France A1 - Deleuze, Jean-Francois A1 - Deloukas, Panos A1 - Tzourio, Christophe A1 - Dartigues, Jean-François A1 - Berr, Claudine A1 - Taylor, Kent D A1 - Civelek, Mete A1 - Eriksson, Per A1 - Psaty, Bruce M A1 - Houwing-Duitermaat, Jeanine A1 - Goodall, Alison H A1 - Cambien, Francois A1 - Kraft, Peter A1 - Amouyel, Philippe A1 - Samani, Nilesh J A1 - Basu, Saonli A1 - Ridker, Paul M A1 - Rosendaal, Frits R A1 - Kabrhel, Christopher A1 - Folsom, Aaron R A1 - Heit, John A1 - Reitsma, Pieter H A1 - Trégouët, David-Alexandre A1 - Smith, Nicholas L A1 - Morange, Pierre-Emmanuel KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Membrane Glycoproteins KW - Membrane Transport Proteins KW - Odds Ratio KW - Tetraspanins KW - Venous Thromboembolism AB -

Venous 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.

VL - 96 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25772935?dopt=Abstract ER - TY - JOUR T1 - Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. JF - Stroke Y1 - 2015 A1 - Carty, Cara L A1 - Keene, Keith L A1 - Cheng, Yu-Ching A1 - Meschia, James F A1 - Chen, Wei-Min A1 - Nalls, Mike A1 - Bis, Joshua C A1 - Kittner, Steven J A1 - Rich, Stephen S A1 - Tajuddin, Salman A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Langefeld, Carl D A1 - Gottesman, Rebecca A1 - Mosley, Thomas H A1 - Shahar, Eyal A1 - Woo, Daniel A1 - Yaffe, Kristine A1 - Liu, Yongmei A1 - Sale, Michèle M A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Longstreth, W T A1 - Mitchell, Braxton D A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Reiner, Alexander A1 - Worrall, Bradford B A1 - Fornage, Myriam KW - African Americans KW - Case-Control Studies KW - Cohort Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke AB -

BACKGROUND 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.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract ER - TY - JOUR T1 - Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Ikram, M Kamran A1 - Adams, Hieab H A1 - Beecham, Ashley H A1 - Rajan, Kumar B A1 - Lopez, Lorna M A1 - Barral, Sandra A1 - van Buchem, Mark A A1 - van der Grond, Jeroen A1 - Smith, Albert V A1 - Hegenscheid, Katrin A1 - Aggarwal, Neelum T A1 - de Andrade, Mariza A1 - Atkinson, Elizabeth J A1 - Beekman, Marian A1 - Beiser, Alexa S A1 - Blanton, Susan H A1 - Boerwinkle, Eric A1 - Brickman, Adam M A1 - Bryan, R Nick A1 - Chauhan, Ganesh A1 - Chen, Christopher P L H A1 - Chouraki, Vincent A1 - de Craen, Anton J M A1 - Crivello, Fabrice A1 - Deary, Ian J A1 - Deelen, Joris A1 - De Jager, Philip L A1 - Dufouil, Carole A1 - Elkind, Mitchell S V A1 - Evans, Denis A A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Guðnason, Vilmundur A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hilal, Saima A1 - Hofer, Edith A1 - Hofman, Albert A1 - Ibrahim-Verbaas, Carla A A1 - Knopman, David S A1 - Lewis, Cora E A1 - Liao, Jiemin A1 - Liewald, David C M A1 - Luciano, Michelle A1 - van der Lugt, Aad A1 - Martinez, Oliver O A1 - Mayeux, Richard A1 - Mazoyer, Bernard A1 - Nalls, Mike A1 - Nauck, Matthias A1 - Niessen, Wiro J A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - von Sarnowski, Bettina A1 - Schmidt, Helena A1 - Schreiner, Pamela J A1 - Schuur, Maaike A1 - Sidney, Stephen S A1 - Sigurdsson, Sigurdur A1 - Slagboom, P Eline A1 - Stott, David J M A1 - van Swieten, John C A1 - Teumer, Alexander A1 - Töglhofer, Anna Maria A1 - Traylor, Matthew A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Tzourio, Christophe A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Wang, Jing J A1 - Wong, Tien Y A1 - Wardlaw, Joanna M A1 - Windham, B Gwen A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wright, Clinton B A1 - Yang, Qiong A1 - Zhao, Wei A1 - Zijdenbos, Alex A1 - Jukema, J Wouter A1 - Sacco, Ralph L A1 - Kardia, Sharon L R A1 - Amouyel, Philippe A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - DeCarli, Charles C A1 - van Duijn, Cornelia M A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Grabe, Hans J A1 - Seshadri, Sudha S A1 - Ikram, M Arfan A1 - Fornage, Myriam KW - Aged KW - Aged, 80 and over KW - Chromosomes, Human KW - Continental Population Groups KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Models, Genetic KW - Stroke KW - White Matter AB -

BACKGROUND: 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.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. JF - Mol Psychiatry Y1 - 2015 A1 - Gottlieb, D J A1 - Hek, K A1 - Chen, T-H A1 - Watson, N F A1 - Eiriksdottir, G A1 - Byrne, E M A1 - Cornelis, M A1 - Warby, S C A1 - Bandinelli, S A1 - Cherkas, L A1 - Evans, D S A1 - Grabe, H J A1 - Lahti, J A1 - Li, M A1 - Lehtimäki, T A1 - Lumley, T A1 - Marciante, K D A1 - Pérusse, L A1 - Psaty, B M A1 - Robbins, J A1 - Tranah, G J A1 - Vink, J M A1 - Wilk, J B A1 - Stafford, J M A1 - Bellis, C A1 - Biffar, R A1 - Bouchard, C A1 - Cade, B A1 - Curhan, G C A1 - Eriksson, J G A1 - Ewert, R A1 - Ferrucci, L A1 - Fülöp, T A1 - Gehrman, P R A1 - Goodloe, R A1 - Harris, T B A1 - Heath, A C A1 - Hernandez, D A1 - Hofman, A A1 - Hottenga, J-J A1 - Hunter, D J A1 - Jensen, M K A1 - Johnson, A D A1 - Kähönen, M A1 - Kao, L A1 - Kraft, P A1 - Larkin, E K A1 - Lauderdale, D S A1 - Luik, A I A1 - Medici, M A1 - Montgomery, G W A1 - Palotie, A A1 - Patel, S R A1 - Pistis, G A1 - Porcu, E A1 - Quaye, L A1 - Raitakari, O A1 - Redline, S A1 - Rimm, E B A1 - Rotter, J I A1 - Smith, A V A1 - Spector, T D A1 - Teumer, A A1 - Uitterlinden, A G A1 - Vohl, M-C A1 - Widen, E A1 - Willemsen, G A1 - Young, T A1 - Zhang, X A1 - Liu, Y A1 - Blangero, J A1 - Boomsma, D I A1 - Gudnason, V A1 - Hu, F A1 - Mangino, M A1 - Martin, N G A1 - O'Connor, G T A1 - Stone, K L A1 - Tanaka, T A1 - Viikari, J A1 - Gharib, S A A1 - Punjabi, N M A1 - Räikkönen, K A1 - Völzke, H A1 - Mignot, E A1 - Tiemeier, H KW - Adult KW - African Americans KW - Aged KW - Dyssomnias KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Self Report KW - Sleep AB -

Usual 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.

VL - 20 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25469926?dopt=Abstract ER - TY - JOUR T1 - NT-proBNP and troponin T and risk of rapid kidney function decline and incident CKD in elderly adults. JF - Clin J Am Soc Nephrol Y1 - 2015 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - Dalrymple, Lorien A1 - de Boer, Ian A1 - DeFilippi, Christopher A1 - Kestenbaum, Bryan A1 - Park, Meyeon A1 - Sarnak, Mark A1 - Seliger, Stephen A1 - Shlipak, Michael KW - Age Factors KW - Aged KW - Aging KW - Biomarkers KW - Cystatin C KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Incidence KW - Kidney KW - Linear Models KW - Longitudinal Studies KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Time Factors KW - Troponin T KW - United States KW - Up-Regulation AB -

BACKGROUND 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.

VL - 10 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25605700?dopt=Abstract ER - TY - JOUR T1 - Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan. JF - Arterioscler Thromb Vasc Biol Y1 - 2015 A1 - Durda, Peter A1 - Sabourin, Jeremy A1 - Lange, Ethan M A1 - Nalls, Mike A A1 - Mychaleckyj, Josyf C A1 - Jenny, Nancy Swords A1 - Li, Jin A1 - Walston, Jeremy A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Valdar, William A1 - Liu, Yongmei A1 - Cushman, Mary A1 - Reiner, Alex P A1 - Tracy, Russell P A1 - Lange, Leslie A KW - Adult KW - African Americans KW - Age Distribution KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Interleukin-2 Receptor alpha Subunit KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Sex Distribution KW - Survival Analysis AB -

OBJECTIVE: 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.

VL - 35 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26293465?dopt=Abstract ER - TY - JOUR T1 - Population genomic analysis of 962 whole genome sequences of humans reveals natural selection in non-coding regions. JF - PLoS One Y1 - 2015 A1 - Yu, Fuli A1 - Lu, Jian A1 - Liu, Xiaoming A1 - Gazave, Elodie A1 - Chang, Diana A1 - Raj, Srilakshmi A1 - Hunter-Zinck, Haley A1 - Blekhman, Ran A1 - Arbiza, Leonardo A1 - Van Hout, Cris A1 - Morrison, Alanna A1 - Johnson, Andrew D A1 - Bis, Joshua A1 - Cupples, L Adrienne A1 - Psaty, Bruce M A1 - Muzny, Donna A1 - Yu, Jin A1 - Gibbs, Richard A A1 - Keinan, Alon A1 - Clark, Andrew G A1 - Boerwinkle, Eric KW - DNA, Intergenic KW - Genetic Loci KW - Humans KW - Metagenomics KW - Open Reading Frames KW - Polymorphism, Single Nucleotide AB -

Whole 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.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25807536?dopt=Abstract ER - TY - JOUR T1 - Predicting Future Years of Life, Health, and Functional Ability: A Healthy Life Calculator for Older Adults. JF - Gerontol Geriatr Med Y1 - 2015 A1 - Diehr, Paula A1 - Diehr, Michael A1 - Arnold, Alice A1 - Yee, Laura M A1 - Odden, Michelle C A1 - Hirsch, Calvin H A1 - Thielke, Stephen A1 - Psaty, Bruce M A1 - Johnson, W Craig A1 - Kizer Md, Jorge R A1 - Newman, Anne AB -

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.

VL - 1 ER - TY - JOUR T1 - Prognostic Significance of High-Sensitivity Cardiac Troponin T Concentrations between the Limit of Blank and Limit of Detection in Community-Dwelling Adults: A Metaanalysis. JF - Clin Chem Y1 - 2015 A1 - Parikh, Ravi H A1 - Seliger, Stephen L A1 - de Lemos, James A1 - Nambi, Vijay A1 - Christenson, Robert A1 - Ayers, Colby A1 - Sun, Wensheng A1 - Gottdiener, John S A1 - Kuller, Lewis H A1 - Ballantyne, Christie A1 - deFilippi, Christopher R KW - Aged KW - Atherosclerosis KW - Biomarkers KW - Cross-Sectional Studies KW - Female KW - Heart Failure KW - Humans KW - Independent Living KW - Limit of Detection KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Prognosis KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Troponin T AB -

BACKGROUND: 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).

VL - 61 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26506994?dopt=Abstract ER - TY - JOUR T1 - Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE). JF - Am J Hematol Y1 - 2015 A1 - Folsom, Aaron R A1 - Tang, Weihong A1 - Roetker, Nicholas S A1 - Heckbert, Susan R A1 - Cushman, Mary A1 - Pankow, James S KW - African Americans KW - Aged KW - Alleles KW - European Continental Ancestry Group KW - Factor XI KW - Female KW - Gene Expression KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States KW - Venous Thromboembolism AB -

Elevated 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.

VL - 90 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26260105?dopt=Abstract ER - TY - JOUR T1 - Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events. JF - PLoS One Y1 - 2015 A1 - Gijsberts, Crystel M A1 - Groenewegen, Karlijn A A1 - Hoefer, Imo E A1 - Eijkemans, Marinus J C A1 - Asselbergs, Folkert W A1 - Anderson, Todd J A1 - Britton, Annie R A1 - Dekker, Jacqueline M A1 - Engström, Gunnar A1 - Evans, Greg W A1 - de Graaf, Jacqueline A1 - Grobbee, Diederick E A1 - Hedblad, Bo A1 - Holewijn, Suzanne A1 - Ikeda, Ai A1 - Kitagawa, Kazuo A1 - Kitamura, Akihiko A1 - de Kleijn, Dominique P V A1 - Lonn, Eva M A1 - Lorenz, Matthias W A1 - Mathiesen, Ellisiv B A1 - Nijpels, Giel A1 - Okazaki, Shuhei A1 - O'Leary, Daniel H A1 - Pasterkamp, Gerard A1 - Peters, Sanne A E A1 - Polak, Joseph F A1 - Price, Jacqueline F A1 - Robertson, Christine A1 - Rembold, Christopher M A1 - Rosvall, Maria A1 - Rundek, Tatjana A1 - Salonen, Jukka T A1 - Sitzer, Matthias A1 - Stehouwer, Coen D A A1 - Bots, Michiel L A1 - den Ruijter, Hester M KW - Adult KW - Age Distribution KW - Aged KW - Carotid Artery Diseases KW - Carotid Intima-Media Thickness KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Comorbidity KW - Continental Population Groups KW - Diabetes Mellitus KW - Dyslipidemias KW - Ethnic Groups KW - Female KW - Follow-Up Studies KW - Global Health KW - Humans KW - Hypertension KW - Incidence KW - Linear Models KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors KW - Smoking KW - Stroke AB -

BACKGROUND: 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.

VL - 10 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26134404?dopt=Abstract ER - TY - JOUR T1 - Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JF - JAMA Neurol Y1 - 2015 A1 - Auer, Paul L A1 - Nalls, Mike A1 - Meschia, James F A1 - Worrall, Bradford B A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Kooperberg, Charles A1 - Burger, Kathleen M A1 - Carlson, Christopher S A1 - Carty, Cara L A1 - Chen, Wei-Min A1 - Cupples, L Adrienne A1 - DeStefano, Anita L A1 - Fornage, Myriam A1 - Hardy, John A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Jarvik, Gail P A1 - Kim, Daniel S A1 - Lakshminarayan, Kamakshi A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Quinlan, Aaron R A1 - Singleton, Andrew B A1 - Thornton, Timothy A A1 - Nickerson, Deborah A A1 - Peters, Ulrike A1 - Rich, Stephen S KW - Aged KW - Brain Ischemia KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Muscle Proteins KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nuclear Proteins KW - Open Reading Frames KW - Palmitoyl-CoA Hydrolase KW - Stroke KW - United States AB -

IMPORTANCE: 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.

VL - 72 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract ER - TY - JOUR T1 - Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. JF - Blood Y1 - 2015 A1 - Huffman, Jennifer E A1 - de Vries, Paul S A1 - Morrison, Alanna C A1 - Sabater-Lleal, Maria A1 - Kacprowski, Tim A1 - Auer, Paul L A1 - Brody, Jennifer A A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Guo, Xiuqing A1 - Lin, Li-An A1 - Marioni, Riccardo E A1 - Müller-Nurasyid, Martina A1 - Yanek, Lisa R A1 - Pankratz, Nathan A1 - Grove, Megan L A1 - de Maat, Moniek P M A1 - Cushman, Mary A1 - Wiggins, Kerri L A1 - Qi, Lihong A1 - Sennblad, Bengt A1 - Harris, Sarah E A1 - Polasek, Ozren A1 - Riess, Helene A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Goel, Anuj A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - Yao, Jie A1 - Tang, Weihong A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Becker, Diane M A1 - Folsom, Aaron R A1 - Giulianini, Franco A1 - Greinacher, Andreas A1 - Hofman, Albert A1 - Huang, Chiang-Ching A1 - Kooperberg, Charles A1 - Silveira, Angela A1 - Starr, John M A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Wright, Alan F A1 - McKnight, Barbara A1 - Franco, Oscar H A1 - Zakai, Neil A1 - Mathias, Rasika A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Tofler, Geoffrey H A1 - Völker, Uwe A1 - Watkins, Hugh A1 - Fornage, Myriam A1 - Hamsten, Anders A1 - Deary, Ian J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Dehghan, Abbas A1 - Reiner, Alex P A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels KW - von Willebrand Factor AB -

Fibrinogen, 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.

VL - 126 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract ER - TY - JOUR T1 - Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. JF - Neurology Y1 - 2015 A1 - Malik, Rainer A1 - Freilinger, Tobias A1 - Winsvold, Bendik S A1 - Anttila, Verneri A1 - Vander Heiden, Jason A1 - Traylor, Matthew A1 - de Vries, Boukje A1 - Holliday, Elizabeth G A1 - Terwindt, Gisela M A1 - Sturm, Jonathan A1 - Bis, Joshua C A1 - Hopewell, Jemma C A1 - Ferrari, Michel D A1 - Rannikmae, Kristiina A1 - Wessman, Maija A1 - Kallela, Mikko A1 - Kubisch, Christian A1 - Fornage, Myriam A1 - Meschia, James F A1 - Lehtimäki, Terho A1 - Sudlow, Cathie A1 - Clarke, Robert A1 - Chasman, Daniel I A1 - Mitchell, Braxton D A1 - Maguire, Jane A1 - Kaprio, Jaakko A1 - Farrall, Martin A1 - Raitakari, Olli T A1 - Kurth, Tobias A1 - Ikram, M Arfan A1 - Reiner, Alex P A1 - Longstreth, W T A1 - Rothwell, Peter M A1 - Strachan, David P A1 - Sharma, Pankaj A1 - Seshadri, Sudha A1 - Quaye, Lydia A1 - Cherkas, Lynn A1 - Schürks, Markus A1 - Rosand, Jonathan A1 - Ligthart, Lannie A1 - Boncoraglio, Giorgio B A1 - Davey Smith, George A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Nyholt, Dale R A1 - Markus, Hugh S A1 - van den Maagdenberg, Arn M J M A1 - Cotsapas, Chris A1 - Zwart, John A A1 - Palotie, Aarno A1 - Dichgans, Martin KW - Brain Ischemia KW - Genome-Wide Association Study KW - Humans KW - Migraine with Aura KW - Migraine without Aura KW - Stroke AB -

OBJECTIVE: 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.

VL - 84 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25934857?dopt=Abstract ER - TY - JOUR T1 - Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study. JF - Diabetes Care Y1 - 2015 A1 - Strand, Linn Beate A1 - Carnethon, Mercedes A1 - Biggs, Mary Lou A1 - Djoussé, Luc A1 - Kaplan, Robert C A1 - Siscovick, David S A1 - Robbins, John A A1 - Redline, Susan A1 - Patel, Sanjay R A1 - Janszky, Imre A1 - Mukamal, Kenneth J KW - Adult KW - Aged KW - Blood Glucose KW - Cardiovascular System KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Tolerance Test KW - Humans KW - Incidence KW - Insulin KW - Insulin Resistance KW - Male KW - Middle Aged KW - Sleep Apnea Syndromes KW - Sleep Initiation and Maintenance Disorders KW - Snoring KW - United States AB -

OBJECTIVE: 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.

VL - 38 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26384390?dopt=Abstract ER - TY - JOUR T1 - Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis. JF - J Clin Endocrinol Metab Y1 - 2015 A1 - Chaker, Layal A1 - Baumgartner, Christine A1 - den Elzen, Wendy P J A1 - Ikram, M Arfan A1 - Blum, Manuel R A1 - Collet, Tinh-Hai A1 - Bakker, Stephan J L A1 - Dehghan, Abbas A1 - Drechsler, Christiane A1 - Luben, Robert N A1 - Hofman, Albert A1 - Portegies, Marileen L P A1 - Medici, Marco A1 - Iervasi, Giorgio A1 - Stott, David J A1 - Ford, Ian A1 - Bremner, Alexandra A1 - Wanner, Christoph A1 - Ferrucci, Luigi A1 - Newman, Anne B A1 - Dullaart, Robin P A1 - Sgarbi, José A A1 - Ceresini, Graziano A1 - Maciel, Rui M B A1 - Westendorp, Rudi G A1 - Jukema, J Wouter A1 - Imaizumi, Misa A1 - Franklyn, Jayne A A1 - Bauer, Douglas C A1 - Walsh, John P A1 - Razvi, Salman A1 - Khaw, Kay-Tee A1 - Cappola, Anne R A1 - Völzke, Henry A1 - Franco, Oscar H A1 - Gussekloo, Jacobijn A1 - Rodondi, Nicolas A1 - Peeters, Robin P KW - Adult KW - Asymptomatic Diseases KW - Female KW - Humans KW - Hypothyroidism KW - Incidence KW - Male KW - Risk Factors KW - Stroke KW - Thyrotropin AB -

OBJECTIVE: 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.

VL - 100 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25856213?dopt=Abstract ER - TY - JOUR T1 - Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JF - JAMA Y1 - 2015 A1 - Blum, Manuel R A1 - Bauer, Douglas C A1 - Collet, Tinh-Hai A1 - Fink, Howard A A1 - Cappola, Anne R A1 - da Costa, Bruno R A1 - Wirth, Christina D A1 - Peeters, Robin P A1 - Asvold, Bjørn O A1 - den Elzen, Wendy P J A1 - Luben, Robert N A1 - Imaizumi, Misa A1 - Bremner, Alexandra P A1 - Gogakos, Apostolos A1 - Eastell, Richard A1 - Kearney, Patricia M A1 - Strotmeyer, Elsa S A1 - Wallace, Erin R A1 - Hoff, Mari A1 - Ceresini, Graziano A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Stott, David J A1 - Westendorp, Rudi G J A1 - Khaw, Kay-Tee A1 - Langhammer, Arnuf A1 - Ferrucci, Luigi A1 - Gussekloo, Jacobijn A1 - Williams, Graham R A1 - Walsh, John P A1 - Jüni, Peter A1 - Aujesky, Drahomir A1 - Rodondi, Nicolas KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Female KW - Fractures, Bone KW - Hip Fractures KW - Humans KW - Hyperthyroidism KW - Hypothyroidism KW - Male KW - Middle Aged KW - Risk Factors KW - Spinal Fractures KW - Thyrotropin KW - Young Adult AB -

IMPORTANCE: 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.

VL - 313 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26010634?dopt=Abstract ER - TY - JOUR T1 - Thyroid function in the euthyroid range and adverse outcomes in older adults. JF - J Clin Endocrinol Metab Y1 - 2015 A1 - Cappola, Anne R A1 - Arnold, Alice M A1 - Wulczyn, Kendra A1 - Carlson, Michelle A1 - Robbins, John A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Aging KW - Atrial Fibrillation KW - Cause of Death KW - Coronary Disease KW - Dementia KW - Female KW - Heart Failure KW - Hip Fractures KW - Humans KW - Incidence KW - Male KW - Prognosis KW - Reference Values KW - Survival Analysis KW - Thyroid Function Tests KW - Thyroid Gland AB -

CONTEXT: 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.

VL - 100 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25514105?dopt=Abstract ER - TY - JOUR T1 - Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. JF - JAMA Intern Med Y1 - 2015 A1 - Asvold, Bjørn O A1 - Vatten, Lars J A1 - Bjøro, Trine A1 - Bauer, Douglas C A1 - Bremner, Alexandra A1 - Cappola, Anne R A1 - Ceresini, Graziano A1 - den Elzen, Wendy P J A1 - Ferrucci, Luigi A1 - Franco, Oscar H A1 - Franklyn, Jayne A A1 - Gussekloo, Jacobijn A1 - Iervasi, Giorgio A1 - Imaizumi, Misa A1 - Kearney, Patricia M A1 - Khaw, Kay-Tee A1 - Maciel, Rui M B A1 - Newman, Anne B A1 - Peeters, Robin P A1 - Psaty, Bruce M A1 - Razvi, Salman A1 - Sgarbi, José A A1 - Stott, David J A1 - Trompet, Stella A1 - Vanderpump, Mark P J A1 - Völzke, Henry A1 - Walsh, John P A1 - Westendorp, Rudi G J A1 - Rodondi, Nicolas KW - Cohort Studies KW - Coronary Disease KW - Humans KW - Hypothyroidism KW - Thyrotropin AB -

IMPORTANCE: 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.

VL - 175 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25893284?dopt=Abstract ER - TY - JOUR T1 - Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults. JF - Heart Y1 - 2015 A1 - Floyd, James S A1 - Sitlani, Colleen M A1 - Wiggins, Kerri L A1 - Wallace, Erin A1 - Suchy-Dicey, Astrid A1 - Abbasi, Siddique A A1 - Carnethon, Mercedes R A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - McKnight, Barbara A1 - Rice, Kenneth M A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Heart Rate KW - Humans KW - Incidence KW - Linear Models KW - Male KW - Myocardial Infarction KW - Outcome Assessment (Health Care) KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Rest KW - Risk Factors KW - Time KW - Washington AB -

OBJECTIVE: 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.

VL - 101 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25214500?dopt=Abstract ER - TY - JOUR T1 - Ventricular Ectopy as a Predictor of Heart Failure and Death. JF - J Am Coll Cardiol Y1 - 2015 A1 - Dukes, Jonathan W A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Mandyam, Mala C A1 - Heckbert, Susan R A1 - Siscovick, David S A1 - Stein, Phyllis K A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Gottdiener, John S A1 - Marcus, Gregory M KW - Aged KW - Catheter Ablation KW - Echocardiography KW - Electrocardiography, Ambulatory KW - Female KW - Forecasting KW - Heart Failure KW - Humans KW - Male KW - Risk Factors KW - Stroke Volume KW - Ventricular Premature Complexes AB -

BACKGROUND: 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.

VL - 66 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26160626?dopt=Abstract ER - TY - JOUR T1 - White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. JF - Stroke Y1 - 2015 A1 - Hofer, Edith A1 - Cavalieri, Margherita A1 - Bis, Joshua C A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Sigurdsson, Sigurdur A1 - Srikanth, Velandai A1 - Trompet, Stella A1 - Verhaaren, Benjamin F J A1 - Wolf, Christiane A1 - Yang, Qiong A1 - Adams, Hieab H H A1 - Amouyel, Philippe A1 - Beiser, Alexa A1 - Buckley, Brendan M A1 - Callisaya, Michele A1 - Chauhan, Ganesh A1 - de Craen, Anton J M A1 - Dufouil, Carole A1 - van Duijn, Cornelia M A1 - Ford, Ian A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Gudnason, Vilmundur A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Martinez, Oliver A1 - Mazoyer, Bernard A1 - Moran, Chris A1 - Niessen, Wiro J A1 - Phan, Thanh A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Sattar, Naveed A1 - Schilling, Sabrina A1 - Shibata, Dean K A1 - Slagboom, P Eline A1 - Smith, Albert A1 - Stott, David J A1 - Taylor, Kent D A1 - Thomson, Russell A1 - Töglhofer, Anna M A1 - Tzourio, Christophe A1 - van Buchem, Mark A1 - Wang, Jing A1 - Westendorp, Rudi G J A1 - Windham, B Gwen A1 - Vernooij, Meike W A1 - Zijdenbos, Alex A1 - Beare, Richard A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Launer, Lenore J A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Schmidt, Helena A1 - Schmidt, Reinhold KW - Adult KW - Aged KW - Cohort Studies KW - Disease Progression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Middle Aged KW - Prospective Studies KW - White Matter AB -

BACKGROUND 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.

VL - 46 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract ER - TY - JOUR T1 - -3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies JF - JAMA Intern Med Y1 - 2016 A1 - Del Gobbo, L. C. A1 - Imamura, F. A1 - Aslibekyan, S. A1 - Marklund, M. A1 - Virtanen, J. K. A1 - Wennberg, M. A1 - Yakoob, M. Y. A1 - Chiuve, S. E. A1 - Dela Cruz, L. A1 - Frazier-Wood, A. C. A1 - Fretts, A. M. A1 - Guallar, E. A1 - Matsumoto, C. A1 - Prem, K. A1 - Tanaka, T. A1 - Wu, J. H. A1 - Zhou, X. A1 - Helmer, C. A1 - Ingelsson, E. A1 - Yuan, J. M. A1 - Barberger-Gateau, P. A1 - Campos, H. A1 - Chaves, P. H. A1 - é, L. A1 - Giles, G. G. A1 - mez-Aracena, J. A1 - Hodge, A. M. A1 - Hu, F. B. A1 - Jansson, J. H. A1 - Johansson, I. A1 - Khaw, K. T. A1 - Koh, W. P. A1 - Lemaitre, R. N. A1 - Lind, L. A1 - Luben, R. N. A1 - Rimm, E. B. A1 - rus, U. A1 - Samieri, C. A1 - Franks, P. W. A1 - Siscovick, D. S. A1 - Stampfer, M. A1 - Steffen, L. M. A1 - Steffen, B. T. A1 - Tsai, M. Y. A1 - van Dam, R. M. A1 - Voutilainen, S. A1 - Willett, W. C. A1 - Woodward, M. A1 - Mozaffarian, D. AB - -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. VL - 176 ER - TY - JOUR T1 - 52 Genetic Loci Influencing Myocardial Mass. JF - J Am Coll Cardiol Y1 - 2016 A1 - van der Harst, Pim A1 - van Setten, Jessica A1 - Verweij, Niek A1 - Vogler, Georg A1 - Franke, Lude A1 - Maurano, Matthew T A1 - Wang, Xinchen A1 - Mateo Leach, Irene A1 - Eijgelsheim, Mark A1 - Sotoodehnia, Nona A1 - Hayward, Caroline A1 - Sorice, Rossella A1 - Meirelles, Osorio A1 - Lyytikäinen, Leo-Pekka A1 - Polasek, Ozren A1 - Tanaka, Toshiko A1 - Arking, Dan E A1 - Ulivi, Sheila A1 - Trompet, Stella A1 - Müller-Nurasyid, Martina A1 - Smith, Albert V A1 - Dörr, Marcus A1 - Kerr, Kathleen F A1 - Magnani, Jared W A1 - del Greco M, Fabiola A1 - Zhang, Weihua A1 - Nolte, Ilja M A1 - Silva, Claudia T A1 - Padmanabhan, Sandosh A1 - Tragante, Vinicius A1 - Esko, Tõnu A1 - Abecasis, Goncalo R A1 - Adriaens, Michiel E A1 - Andersen, Karl A1 - Barnett, Phil A1 - Bis, Joshua C A1 - Bodmer, Rolf A1 - Buckley, Brendan M A1 - Campbell, Harry A1 - Cannon, Megan V A1 - Chakravarti, Aravinda A1 - Chen, Lin Y A1 - Delitala, Alessandro A1 - Devereux, Richard B A1 - Doevendans, Pieter A A1 - Dominiczak, Anna F A1 - Ferrucci, Luigi A1 - Ford, Ian A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Haugen, Eric A1 - Heinig, Matthias A1 - Hernandez, Dena G A1 - Hillege, Hans L A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hubner, Norbert A1 - Hwang, Shih-Jen A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kellis, Manolis A1 - Kolcic, Ivana A1 - Kooner, Ishminder K A1 - Kooner, Jaspal S A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Lage, Kasper A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Lundby, Alicia A1 - Macfarlane, Peter W A1 - May, Dalit A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Nappo, Stefania A1 - Naitza, Silvia A1 - Neph, Shane A1 - Nord, Alex S A1 - Nutile, Teresa A1 - Okin, Peter M A1 - Olsen, Jesper V A1 - Oostra, Ben A A1 - Penninger, Josef M A1 - Pennacchio, Len A A1 - Pers, Tune H A1 - Perz, Siegfried A1 - Peters, Annette A1 - Pinto, Yigal M A1 - Pfeufer, Arne A1 - Pilia, Maria Grazia A1 - Pramstaller, Peter P A1 - Prins, Bram P A1 - Raitakari, Olli T A1 - Raychaudhuri, Soumya A1 - Rice, Ken M A1 - Rossin, Elizabeth J A1 - Rotter, Jerome I A1 - Schafer, Sebastian A1 - Schlessinger, David A1 - Schmidt, Carsten O A1 - Sehmi, Jobanpreet A1 - Silljé, Herman H W A1 - Sinagra, Gianfranco A1 - Sinner, Moritz F A1 - Slowikowski, Kamil A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Spiering, Wilko A1 - Stamatoyannopoulos, John A A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tan, Sian-Tsung A1 - Tarasov, Kirill V A1 - Trinh, Bosco A1 - Uitterlinden, André G A1 - van den Boogaard, Malou A1 - van Duijn, Cornelia M A1 - van Gilst, Wiek H A1 - Viikari, Jorma S A1 - Visscher, Peter M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Weichenberger, Christian X A1 - Westra, Harm-Jan A1 - Wijmenga, Cisca A1 - Wolffenbuttel, Bruce H A1 - Yang, Jian A1 - Bezzina, Connie R A1 - Munroe, Patricia B A1 - Snieder, Harold A1 - Wright, Alan F A1 - Rudan, Igor A1 - Boyer, Laurie A A1 - Asselbergs, Folkert W A1 - van Veldhuisen, Dirk J A1 - Stricker, Bruno H A1 - Psaty, Bruce M A1 - Ciullo, Marina A1 - Sanna, Serena A1 - Lehtimäki, Terho A1 - Wilson, James F A1 - Bandinelli, Stefania A1 - Alonso, Alvaro A1 - Gasparini, Paolo A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Gudnason, Vilmundur A1 - Felix, Stephan B A1 - Heckbert, Susan R A1 - de Boer, Rudolf A A1 - Newton-Cheh, Christopher A1 - Hicks, Andrew A A1 - Chambers, John C A1 - Jamshidi, Yalda A1 - Visel, Axel A1 - Christoffels, Vincent M A1 - Isaacs, Aaron A1 - Samani, Nilesh J A1 - de Bakker, Paul I W AB -

BACKGROUND: 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.

VL - 68 IS - 13 ER - TY - JOUR T1 - Agreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies. JF - Growth Horm IGF Res Y1 - 2016 A1 - Aneke-Nash, Chino S A1 - Dominguez-Islas, Clara A1 - Bůzková, Petra A1 - Qi, Qibin A1 - Xue, XiaoNan A1 - Pollak, Michael A1 - Strickler, Howard D A1 - Kaplan, Robert C AB -

OBJECTIVE: 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.

VL - 26 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26774400?dopt=Abstract ER - TY - JOUR T1 - APOL1 Genotype, Kidney and Cardiovascular Disease, and Death in Older Adults. JF - Arterioscler Thromb Vasc Biol Y1 - 2016 A1 - Mukamal, Kenneth J A1 - Tremaglio, Joseph A1 - Friedman, David J A1 - Ix, Joachim H A1 - Kuller, Lewis H A1 - Tracy, Russell P A1 - Pollak, Martin R KW - African Americans KW - Age Factors KW - Aged KW - Albuminuria KW - Apolipoproteins KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cause of Death KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Health Status Disparities KW - Heterozygote KW - Homozygote KW - Humans KW - Incidence KW - Kaplan-Meier Estimate KW - Kidney Diseases KW - Lipoproteins, HDL KW - Male KW - Myocardial Infarction KW - Phenotype KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: 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.

VL - 36 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26634651?dopt=Abstract ER - TY - JOUR T1 - Association of the IGF1 gene with fasting insulin levels. JF - Eur J Hum Genet Y1 - 2016 A1 - Willems, Sara M A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Morrison, Alanna C A1 - Lipovich, Leonard A1 - Dauriz, Marco A1 - Chen, Yuning A1 - Liu, Ching-Ti A1 - Rybin, Denis V A1 - Gibbs, Richard A A1 - Muzny, Donna A1 - Pankow, James S A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Vasan, Ramachandran S A1 - Kaplan, Robert C A1 - Isaacs, Aaron A1 - Dupuis, Josée A1 - van Duijn, Cornelia M A1 - Meigs, James B AB -

Insulin-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.

VL - 24 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26860063?dopt=Abstract ER - TY - JOUR T1 - Associations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length. JF - J Nutr Y1 - 2016 A1 - Fretts, Amanda M A1 - Mozaffarian, Dariush A1 - Siscovick, David S A1 - King, Irena B A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Rimm, Eric B A1 - Sitlani, Colleen A1 - Sacks, Frank M A1 - Song, Xiaoling A1 - Sotoodehnia, Nona A1 - Spiegelman, Donna A1 - Lemaitre, Rozenn N KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Diet KW - Dietary Fats KW - Eicosanoic Acids KW - Fatty Acids KW - Female KW - Humans KW - Male KW - Mortality KW - Palmitic Acid KW - Phospholipids KW - Prospective Studies KW - Risk Factors KW - Stearic Acids AB -

BACKGROUND: 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.

VL - 146 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26701797?dopt=Abstract ER - TY - JOUR T1 - Brain natriuretic peptide and insulin resistance in older adults. JF - Diabet Med Y1 - 2016 A1 - Kim, F A1 - Biggs, M L A1 - Kizer, J R A1 - Brutsaert, E F A1 - de Fillipi, C A1 - Newman, A B A1 - Kronmal, R A A1 - Tracy, R P A1 - Gottdiener, J S A1 - Djoussé, L A1 - de Boer, I H A1 - Psaty, B M A1 - Siscovick, D S A1 - Mukamal, K J AB -

AIMS: 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.

ER - TY - JOUR T1 - Changes in Depressive Symptoms and Subsequent Risk of Stroke in the Cardiovascular Health Study. JF - Stroke Y1 - 2016 A1 - Gilsanz, Paola A1 - Kubzansky, Laura D A1 - Tchetgen Tchetgen, Eric J A1 - Wang, Qianyi A1 - Kawachi, Ichiro A1 - Patton, Kristen K A1 - Fitzpatrick, Annette L A1 - Kop, Willem J A1 - Longstreth, W T A1 - Glymour, M Maria AB -

BACKGROUND 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.

ER - TY - JOUR T1 - Common variants in DRD2 are associated with sleep duration: the CARe consortium. JF - Hum Mol Genet Y1 - 2016 A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Lauderdale, Diane S A1 - Bennett, David A A1 - Buchman, Aron S A1 - Buxbaum, Sarah G A1 - De Jager, Philip L A1 - Evans, Daniel S A1 - Fulop, Tibor A1 - Gharib, Sina A A1 - Johnson, W Craig A1 - Kim, Hyun A1 - Larkin, Emma K A1 - Lee, Seung Ku A1 - Lim, Andrew S A1 - Punjabi, Naresh M A1 - Shin, Chol A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Weng, Jia A1 - Yaffe, Kristine A1 - Zee, Phyllis C A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Redline, Susan A1 - Saxena, Richa KW - Cohort Studies KW - Ethnic Groups KW - Humans KW - Polymorphism, Single Nucleotide KW - Polysomnography KW - Receptors, Dopamine D2 KW - Sleep KW - Time Factors AB -

Sleep 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.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26464489?dopt=Abstract ER - TY - JOUR T1 - Development and Validation of a Sudden Cardiac Death Prediction Model for the General Population. JF - Circulation Y1 - 2016 A1 - Deo, Rajat A1 - Norby, Faye L A1 - Katz, Ronit A1 - Sotoodehnia, Nona A1 - Adabag, Selcuk A1 - deFilippi, Christopher R A1 - Kestenbaum, Bryan A1 - Chen, Lin Y A1 - Heckbert, Susan R A1 - Folsom, Aaron R A1 - Kronmal, Richard A A1 - Konety, Suma A1 - Patton, Kristen K A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Alonso, Alvaro AB -

BACKGROUND: 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.

VL - 134 IS - 11 ER - TY - JOUR T1 - Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. JF - J Am Coll Cardiol Y1 - 2016 A1 - Khera, Amit V A1 - Won, Hong-Hee A1 - Peloso, Gina M A1 - Lawson, Kim S A1 - Bartz, Traci M A1 - Deng, Xuan A1 - van Leeuwen, Elisabeth M A1 - Natarajan, Pradeep A1 - Emdin, Connor A A1 - Bick, Alexander G A1 - Morrison, Alanna C A1 - Brody, Jennifer A A1 - Gupta, Namrata A1 - Nomura, Akihiro A1 - Kessler, Thorsten A1 - Duga, Stefano A1 - Bis, Joshua C A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Psaty, Bruce A1 - Rader, Daniel J A1 - Danesh, John A1 - Schunkert, Heribert A1 - McPherson, Ruth A1 - Farrall, Martin A1 - Watkins, Hugh A1 - Lander, Eric A1 - Wilson, James G A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Merlini, Piera Angelica A1 - Ardissino, Diego A1 - Saleheen, Danish A1 - Gabriel, Stacey A1 - Kathiresan, Sekar AB -

BACKGROUND: 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.

VL - 67 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27050191?dopt=Abstract ER - TY - JOUR T1 - Digit Symbol Substitution test and future clinical and subclinical disorders of cognition, mobility and mood in older adults. JF - Age Ageing Y1 - 2016 A1 - Rosano, Caterina A1 - Perera, Subashan A1 - Inzitari, Marco A1 - Newman, Anne B A1 - Longstreth, William T A1 - Studenski, Stephanie AB -

OBJECTIVE: 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.

VL - 45 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27496932?dopt=Abstract ER - TY - JOUR T1 - Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. JF - PLoS Genet Y1 - 2016 A1 - Smith, J Gustav A1 - Felix, Janine F A1 - Morrison, Alanna C A1 - Kalogeropoulos, Andreas A1 - Trompet, Stella A1 - Wilk, Jemma B A1 - Gidlöf, Olof A1 - Wang, Xinchen A1 - Morley, Michael A1 - Mendelson, Michael A1 - Joehanes, Roby A1 - Ligthart, Symen A1 - Shan, Xiaoyin A1 - Bis, Joshua C A1 - Wang, Ying A A1 - Sjögren, Marketa A1 - Ngwa, Julius A1 - Brandimarto, Jeffrey A1 - Stott, David J A1 - Aguilar, David A1 - Rice, Kenneth M A1 - Sesso, Howard D A1 - Demissie, Serkalem A1 - Buckley, Brendan M A1 - Taylor, Kent D A1 - Ford, Ian A1 - Yao, Chen A1 - Liu, Chunyu A1 - Sotoodehnia, Nona A1 - van der Harst, Pim A1 - Stricker, Bruno H Ch A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Gaziano, J Michael A1 - Hofman, Albert A1 - Moravec, Christine S A1 - Uitterlinden, André G A1 - Kellis, Manolis A1 - van Meurs, Joyce B A1 - Margulies, Kenneth B A1 - Dehghan, Abbas A1 - Levy, Daniel A1 - Olde, Björn A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Jukema, J Wouter A1 - Djoussé, Luc A1 - Franco, Oscar H A1 - Boerwinkle, Eric A1 - Boyer, Laurie A A1 - Newton-Cheh, Christopher A1 - Butler, Javed A1 - Vasan, Ramachandran S A1 - Cappola, Thomas P A1 - Smith, Nicholas L AB -

Failure 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.

VL - 12 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27149122?dopt=Abstract ER - TY - JOUR T1 - A DNA methylation biomarker of alcohol consumption. JF - Mol Psychiatry Y1 - 2016 A1 - Liu, C A1 - Marioni, R E A1 - Hedman, Å K A1 - Pfeiffer, L A1 - Tsai, P-C A1 - Reynolds, L M A1 - Just, A C A1 - Duan, Q A1 - Boer, C G A1 - Tanaka, T A1 - Elks, C E A1 - Aslibekyan, S A1 - Brody, J A A1 - Kühnel, B A1 - Herder, C A1 - Almli, L M A1 - Zhi, D A1 - Wang, Y A1 - Huan, T A1 - Yao, C A1 - Mendelson, M M A1 - Joehanes, R A1 - Liang, L A1 - Love, S-A A1 - Guan, W A1 - Shah, S A1 - McRae, A F A1 - Kretschmer, A A1 - Prokisch, H A1 - Strauch, K A1 - Peters, A A1 - Visscher, P M A1 - Wray, N R A1 - Guo, X A1 - Wiggins, K L A1 - Smith, A K A1 - Binder, E B A1 - Ressler, K J A1 - Irvin, M R A1 - Absher, D M A1 - Hernandez, D A1 - Ferrucci, L A1 - Bandinelli, S A1 - Lohman, K A1 - Ding, J A1 - Trevisi, L A1 - Gustafsson, S A1 - Sandling, J H A1 - Stolk, L A1 - Uitterlinden, A G A1 - Yet, I A1 - Castillo-Fernandez, J E A1 - Spector, T D A1 - Schwartz, J D A1 - Vokonas, P A1 - Lind, L A1 - Li, Y A1 - Fornage, M A1 - Arnett, D K A1 - Wareham, N J A1 - Sotoodehnia, N A1 - Ong, K K A1 - van Meurs, J B J A1 - Conneely, K N A1 - Baccarelli, A A A1 - Deary, I J A1 - Bell, J T A1 - North, K E A1 - Liu, Y A1 - Waldenberger, M A1 - London, S J A1 - Ingelsson, E A1 - Levy, D AB -

The 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.

ER - TY - JOUR T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. JF - Genome Biol Y1 - 2016 A1 - Ligthart, Symen A1 - Marzi, Carola A1 - Aslibekyan, Stella A1 - Mendelson, Michael M A1 - Conneely, Karen N A1 - Tanaka, Toshiko A1 - Colicino, Elena A1 - Waite, Lindsay L A1 - Joehanes, Roby A1 - Guan, Weihua A1 - Brody, Jennifer A A1 - Elks, Cathy A1 - Marioni, Riccardo A1 - Jhun, Min A A1 - Agha, Golareh A1 - Bressler, Jan A1 - Ward-Caviness, Cavin K A1 - Chen, Brian H A1 - Huan, Tianxiao A1 - Bakulski, Kelly A1 - Salfati, Elias L A1 - Fiorito, Giovanni A1 - Wahl, Simone A1 - Schramm, Katharina A1 - Sha, Jin A1 - Hernandez, Dena G A1 - Just, Allan C A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Pilling, Luke C A1 - Pankow, James S A1 - Tsao, Phil S A1 - Liu, Chunyu A1 - Zhao, Wei A1 - Guarrera, Simonetta A1 - Michopoulos, Vasiliki J A1 - Smith, Alicia K A1 - Peters, Marjolein J A1 - Melzer, David A1 - Vokonas, Pantel A1 - Fornage, Myriam A1 - Prokisch, Holger A1 - Bis, Joshua C A1 - Chu, Audrey Y A1 - Herder, Christian A1 - Grallert, Harald A1 - Yao, Chen A1 - Shah, Sonia A1 - McRae, Allan F A1 - Lin, Honghuang A1 - Horvath, Steve A1 - Fallin, Daniele A1 - Hofman, Albert A1 - Wareham, Nicholas J A1 - Wiggins, Kerri L A1 - Feinberg, Andrew P A1 - Starr, John M A1 - Visscher, Peter M A1 - Murabito, Joanne M A1 - Kardia, Sharon L R A1 - Absher, Devin M A1 - Binder, Elisabeth B A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Matullo, Giuseppe A1 - Schwartz, Joel D A1 - Demerath, Ellen W A1 - Uitterlinden, André G A1 - van Meurs, Joyce B J A1 - Franco, Oscar H A1 - Chen, Yii-Der Ida A1 - Levy, Daniel A1 - Turner, Stephen T A1 - Deary, Ian J A1 - Ressler, Kerry J A1 - Dupuis, Josée A1 - Ferrucci, Luigi A1 - Ong, Ken K A1 - Assimes, Themistocles L A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Arnett, Donna K A1 - Baccarelli, Andrea A A1 - Benjamin, Emelia J A1 - Dehghan, Abbas AB -

BACKGROUND: 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.

VL - 17 IS - 1 ER - TY - JOUR T1 - An 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. JF - Genet Epidemiol Y1 - 2016 A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Manning, Alisa K A1 - Aschard, Hugues A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Boerwinkle, Eric A1 - Brown, Michael R A1 - Morrison, Alanna C A1 - Fornage, Myriam A1 - Lin, Li-An A1 - Richard, Melissa A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Marten, Jonathan A1 - Rudan, Igor A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Province, Michael A A1 - Deng, Xuan A1 - Fisher, Virginia A A1 - Zhou, Yanhua A1 - Bielak, Lawrence F A1 - Smith, Jennifer A1 - Huffman, Jennifer E A1 - Padmanabhan, Sandosh A1 - Smith, Blair H A1 - Ding, Jingzhong A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Bouchard, Claude A1 - Rankinen, Tuomo A1 - Rice, Treva K A1 - Arnett, Donna A1 - Schwander, Karen A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Alfred, Tamuno A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Amin, Najaf A1 - Franco, Oscar H A1 - van Duijn, Cornelia M A1 - Vojinovic, Dina A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Kardia, Sharon A1 - Zhu, Xiaofeng A1 - Rice, Kenneth A1 - Borecki, Ingrid B A1 - Rao, Dabeeru C A1 - Gauderman, W James A1 - Cupples, L Adrienne AB -

Studying 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.

VL - 40 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27230302?dopt=Abstract ER - TY - JOUR T1 - Epigenetic Signatures of Cigarette Smoking. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Joehanes, Roby A1 - Just, Allan C A1 - Marioni, Riccardo E A1 - Pilling, Luke C A1 - Reynolds, Lindsay M A1 - Mandaviya, Pooja R A1 - Guan, Weihua A1 - Xu, Tao A1 - Elks, Cathy E A1 - Aslibekyan, Stella A1 - Moreno-Macias, Hortensia A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Dhingra, Radhika A1 - Yousefi, Paul A1 - Pankow, James S A1 - Kunze, Sonja A1 - Shah, Sonia H A1 - McRae, Allan F A1 - Lohman, Kurt A1 - Sha, Jin A1 - Absher, Devin M A1 - Ferrucci, Luigi A1 - Zhao, Wei A1 - Demerath, Ellen W A1 - Bressler, Jan A1 - Grove, Megan L A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Yao, Chen A1 - Kiel, Douglas P A1 - Peters, Annette A1 - Wang-Sattler, Rui A1 - Visscher, Peter M A1 - Wray, Naomi R A1 - Starr, John M A1 - Ding, Jingzhong A1 - Rodriguez, Carlos J A1 - Wareham, Nicholas J A1 - Irvin, Marguerite R A1 - Zhi, Degui A1 - Barrdahl, Myrto A1 - Vineis, Paolo A1 - Ambatipudi, Srikant A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Schwartz, Joel A1 - Colicino, Elena A1 - Hou, Lifang A1 - Vokonas, Pantel S A1 - Hernandez, Dena G A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Turner, Stephen T A1 - Ware, Erin B A1 - Smith, Alicia K A1 - Klengel, Torsten A1 - Binder, Elisabeth B A1 - Psaty, Bruce M A1 - Taylor, Kent D A1 - Gharib, Sina A A1 - Swenson, Brenton R A1 - Liang, Liming A1 - DeMeo, Dawn L A1 - O'Connor, George T A1 - Herceg, Zdenko A1 - Ressler, Kerry J A1 - Conneely, Karen N A1 - Sotoodehnia, Nona A1 - Kardia, Sharon L R A1 - Melzer, David A1 - Baccarelli, Andrea A A1 - van Meurs, Joyce B J A1 - Romieu, Isabelle A1 - Arnett, Donna K A1 - Ong, Ken K A1 - Liu, Yongmei A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Fornage, Myriam A1 - Levy, Daniel A1 - London, Stephanie J AB -

BACKGROUND: 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.

VL - 9 IS - 5 ER - TY - JOUR T1 - Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. JF - Am J Hum Genet Y1 - 2016 A1 - Chami, Nathalie A1 - Chen, Ming-Huei A1 - Slater, Andrew J A1 - Eicher, John D A1 - Evangelou, Evangelos A1 - Tajuddin, Salman M A1 - Love-Gregory, Latisha A1 - Kacprowski, Tim A1 - Schick, Ursula M A1 - Nomura, Akihiro A1 - Giri, Ayush A1 - Lessard, Samuel A1 - Brody, Jennifer A A1 - Schurmann, Claudia A1 - Pankratz, Nathan A1 - Yanek, Lisa R A1 - Manichaikul, Ani A1 - Pazoki, Raha A1 - Mihailov, Evelin A1 - Hill, W David A1 - Raffield, Laura M A1 - Burt, Amber A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - O'Donoghue, Michelle L A1 - Crosslin, David R A1 - de Denus, Simon A1 - Dubé, Marie-Pierre A1 - Elliott, Paul A1 - Engström, Gunnar A1 - Evans, Michele K A1 - Floyd, James S A1 - Fornage, Myriam A1 - Gao, He A1 - Greinacher, Andreas A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hernesniemi, Jussi A1 - Highland, Heather M A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Li, Jin A1 - Liewald, David C M A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mathias, Rasika A A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mononen, Nina A1 - Nalls, Mike A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - O'Donnell, Chris J A1 - Orho-Melander, Marju A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Polfus, Linda A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Raitoharju, Emma A1 - Richard, Melissa A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schmidt, Frank A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thuesen, Betina H A1 - Torstenson, Eric S A1 - Tracy, Russell P A1 - Tzoulaki, Ioanna A1 - Zakai, Neil A A1 - Vacchi-Suzzi, Caterina A1 - van Duijn, Cornelia M A1 - van Rooij, Frank J A A1 - Cushman, Mary A1 - Deary, Ian J A1 - Velez Edwards, Digna R A1 - Vergnaud, Anne-Claire A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Zonderman, Alan B A1 - Kathiresan, Sekar A1 - Grarup, Niels A1 - Esko, Tõnu A1 - Loos, Ruth J F A1 - Lange, Leslie A A1 - Faraday, Nauder A1 - Abumrad, Nada A A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Auer, Paul L A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Lettre, Guillaume AB -

Red 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.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. JF - Hum Mol Genet Y1 - 2016 A1 - Evans, Daniel S A1 - Avery, Christy L A1 - Nalls, Mike A A1 - Li, Guo A1 - Barnard, John A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Butler, Anne M A1 - Buxbaum, Sarah G A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Berenson, Gerald S A1 - Bis, Joshua C A1 - Buyske, Steven A1 - Carty, Cara L A1 - Chen, Wei A1 - Chung, Mina K A1 - Cummings, Steven R A1 - Deo, Rajat A1 - Eaton, Charles B A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hindorff, Lucia A A1 - Hsueh, Wen-Chi A1 - Isaacs, Aaron A1 - Jamshidi, Yalda A1 - Kerr, Kathleen F A1 - Liu, Felix A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Magnani, Jared W A1 - Maher, Joseph F A1 - Mehra, Reena A1 - Meng, Yan A A1 - Musani, Solomon K A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Shohet, Ralph V A1 - Singleton, Andrew B A1 - Smith, Jonathan D A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Taylor, Herman A A1 - Van Wagoner, David R A1 - Wilson, James G A1 - Young, Taylor A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Tranah, Gregory J A1 - Whitsel, Eric A A1 - Reiner, Alex P A1 - Sotoodehnia, Nona AB -

The 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.

ER - TY - JOUR T1 - Gait Speed Predicts Incident Disability: A Pooled Analysis. JF - J Gerontol A Biol Sci Med Sci Y1 - 2016 A1 - Perera, Subashan A1 - Patel, Kushang V A1 - Rosano, Caterina A1 - Rubin, Susan M A1 - Satterfield, Suzanne A1 - Harris, Tamara A1 - Ensrud, Kristine A1 - Orwoll, Eric A1 - Lee, Christine G A1 - Chandler, Julie M A1 - Newman, Anne B A1 - Cauley, Jane A A1 - Guralnik, Jack M A1 - Ferrucci, Luigi A1 - Studenski, Stephanie A KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Disability Evaluation KW - Disabled Persons KW - Female KW - Gait KW - Geriatric Assessment KW - Humans KW - Independent Living KW - Male KW - Mobility Limitation KW - Predictive Value of Tests KW - Prognosis KW - Psychomotor Performance KW - Risk Assessment KW - Risk Factors KW - ROC Curve KW - Survival Analysis KW - United States AB -

BACKGROUND: 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.

VL - 71 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26297942?dopt=Abstract ER - TY - JOUR T1 - {Gene-gene Interaction Analyses for Atrial Fibrillation JF - Sci Rep Y1 - 2016 A1 - Lin, H. A1 - Mueller-Nurasyid, M. A1 - Smith, A. V. A1 - Arking, D. E. A1 - Barnard, J. A1 - Bartz, T. M. A1 - Lunetta, K. L. A1 - Lohman, K. A1 - Kleber, M. E. A1 - Lubitz, S. A. A1 - Geelhoed, B. A1 - Trompet, S. A1 - Niemeijer, M. N. A1 - Kacprowski, T. A1 - Chasman, D. I. A1 - Klarin, D. A1 - Sinner, M. F. A1 - Waldenberger, M. A1 - Meitinger, T. A1 - Harris, T. B. A1 - Launer, L. J. A1 - Soliman, E. Z. A1 - Chen, L. Y. A1 - Smith, J. D. A1 - Van Wagoner, D. R. A1 - Rotter, J. I. A1 - Psaty, B. M. A1 - Xie, Z. A1 - Hendricks, A. E. A1 - Ding, J. A1 - Delgado, G. E. A1 - Verweij, N. A1 - van der Harst, P. A1 - Macfarlane, P. W. A1 - Ford, I. A1 - Hofman, A. A1 - Uitterlinden, A. A1 - Heeringa, J. A1 - Franco, O. H. A1 - Kors, J. A. A1 - Weiss, S. A1 - V?lzke, H. A1 - Rose, L. M. A1 - Natarajan, P. A1 - Kathiresan, S. A1 - K??b, S. A1 - Gudnason, V. A1 - Alonso, A. A1 - Chung, M. K. A1 - Heckbert, S. R. A1 - Benjamin, E. J. A1 - Liu, Y. A1 - M?rz, W. A1 - Rienstra, M. A1 - Jukema, J. W. A1 - Stricker, B. H. A1 - D?rr, M. A1 - Albert, C. M. A1 - Ellinor, P. T. AB - {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: 1.27-1.65 VL - 6 ER - TY - JOUR T1 - General Framework for Meta-Analysis of Haplotype Association Tests. JF - Genet Epidemiol Y1 - 2016 A1 - Wang, Shuai A1 - Zhao, Jing Hua A1 - An, Ping A1 - Guo, Xiuqing A1 - Jensen, Richard A A1 - Marten, Jonathan A1 - Huffman, Jennifer E A1 - Meidtner, Karina A1 - Boeing, Heiner A1 - Campbell, Archie A1 - Rice, Kenneth M A1 - Scott, Robert A A1 - Yao, Jie A1 - Schulze, Matthias B A1 - Wareham, Nicholas J A1 - Borecki, Ingrid B A1 - Province, Michael A A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Dupuis, Josée AB -

For 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.

VL - 40 IS - 3 ER - TY - JOUR T1 - {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function JF - Nat Commun Y1 - 2016 A1 - Pattaro, C. A1 - Teumer, A. A1 - Gorski, M. A1 - Chu, A. Y. A1 - Li, M. A1 - Mijatovic, V. A1 - Garnaas, M. A1 - Tin, A. A1 - Sorice, R. A1 - Li, Y. A1 - Taliun, D. A1 - Olden, M. A1 - Foster, M. A1 - Yang, Q. A1 - Chen, M. H. A1 - Pers, T. H. A1 - Johnson, A. D. A1 - Ko, Y. A. A1 - Fuchsberger, C. A1 - Tayo, B. A1 - Nalls, M. A1 - Feitosa, M. F. A1 - Isaacs, A. A1 - Dehghan, A. A1 - d'Adamo, P. A1 - Adeyemo, A. A1 - Dieffenbach, A. K. A1 - Zonderman, A. B. A1 - Nolte, I. M. A1 - van der Most, P. J. A1 - Wright, A. F. A1 - Shuldiner, A. R. A1 - Morrison, A. C. A1 - Hofman, A. A1 - Smith, A. V. A1 - Dreisbach, A. W. A1 - Franke, A. A1 - Uitterlinden, A. G. A1 - Metspalu, A. A1 - Tonjes, A. A1 - Lupo, A. A1 - Robino, A. A1 - Johansson, ?. A1 - Demirkan, A. A1 - Kollerits, B. A1 - Freedman, B. I. A1 - Ponte, B. A1 - Oostra, B. A. A1 - Paulweber, B. A1 - Kr?mer, B. K. A1 - Mitchell, B. D. A1 - Buckley, B. M. A1 - Peralta, C. A. A1 - Hayward, C. A1 - Helmer, C. A1 - Rotimi, C. N. A1 - Shaffer, C. M. A1 - M?ller, C. A1 - Sala, C. A1 - van Duijn, C. M. A1 - Saint-Pierre, A. A1 - Ackermann, D. A1 - Shriner, D. A1 - Ruggiero, D. A1 - Toniolo, D. A1 - Lu, Y. A1 - Cusi, D. A1 - Czamara, D. A1 - Ellinghaus, D. A1 - Siscovick, D. S. A1 - Ruderfer, D. A1 - Gieger, C. A1 - Grallert, H. A1 - Rochtchina, E. A1 - Atkinson, E. J. A1 - Holliday, E. G. A1 - Boerwinkle, E. A1 - Salvi, E. A1 - Bottinger, E. P. A1 - Murgia, F. A1 - Rivadeneira, F. A1 - Ernst, F. A1 - Kronenberg, F. A1 - Hu, F. B. A1 - Navis, G. J. A1 - Curhan, G. C. A1 - Ehret, G. B. A1 - Homuth, G. A1 - Coassin, S. A1 - Thun, G. A. A1 - Pistis, G. A1 - Gambaro, G. A1 - Malerba, G. A1 - Montgomery, G. W. A1 - Eiriksdottir, G. A1 - Jacobs, G. A1 - Li, G. A1 - Wichmann, H. E. A1 - Campbell, H. A1 - Schmidt, H. A1 - Wallaschofski, H. A1 - V?lzke, H. A1 - Brenner, H. A1 - Kroemer, H. K. A1 - Kramer, H. A1 - Lin, H. A1 - Leach, I. M. A1 - Ford, I. A1 - Guessous, I. A1 - Rudan, I. A1 - Prokopenko, I. A1 - Borecki, I. A1 - Heid, I. M. A1 - Kolcic, I. A1 - Persico, I. A1 - Jukema, J. W. A1 - Wilson, J. F. A1 - Felix, J. F. A1 - Divers, J. A1 - Lambert, J. C. A1 - Stafford, J. M. A1 - Gaspoz, J. M. A1 - Smith, J. A. A1 - Faul, J. D. A1 - Wang, J. J. A1 - Ding, J. A1 - Hirschhorn, J. N. A1 - Attia, J. A1 - Whitfield, J. B. A1 - Chalmers, J. A1 - Viikari, J. A1 - Coresh, J. A1 - Denny, J. C. A1 - Karjalainen, J. A1 - Fernandes, J. K. A1 - Endlich, K. A1 - Butterbach, K. A1 - Keene, K. L. A1 - Lohman, K. A1 - Portas, L. A1 - Launer, L. J. A1 - Lyytik?inen, L. P. A1 - Yengo, L. A1 - Franke, L. A1 - Ferrucci, L. A1 - Rose, L. M. A1 - Kedenko, L. A1 - Rao, M. A1 - Struchalin, M. A1 - Kleber, M. E. A1 - Cavalieri, M. A1 - Haun, M. A1 - Cornelis, M. C. A1 - Ciullo, M. A1 - Pirastu, M. A1 - de Andrade, M. A1 - McEvoy, M. A. A1 - Woodward, M. A1 - Adam, M. A1 - Cocca, M. A1 - Nauck, M. A1 - Imboden, M. A1 - Waldenberger, M. A1 - Pruijm, M. A1 - Metzger, M. A1 - Stumvoll, M. A1 - Evans, M. K. A1 - Sale, M. M. A1 - K?h?nen, M. A1 - Boban, M. A1 - Bochud, M. A1 - Rheinberger, M. A1 - Verweij, N. A1 - Bouatia-Naji, N. A1 - Martin, N. G. A1 - Hastie, N. A1 - Probst-Hensch, N. A1 - Soranzo, N. A1 - Devuyst, O. A1 - Raitakari, O. A1 - Gottesman, O. A1 - Franco, O. H. A1 - Polasek, O. A1 - Gasparini, P. A1 - Munroe, P. B. A1 - Ridker, P. M. A1 - Mitchell, P. A1 - Muntner, P. A1 - Meisinger, C. A1 - Smit, J. H. A1 - Kovacs, P. A1 - Wild, P. S. A1 - Froguel, P. A1 - Rettig, R. A1 - M?gi, R. A1 - Biffar, R. A1 - Schmidt, R. A1 - Middelberg, R. P. A1 - Carroll, R. J. A1 - Penninx, B. W. A1 - Scott, R. J. A1 - Katz, R. A1 - Sedaghat, S. A1 - Wild, S. H. A1 - Kardia, S. L. A1 - Ulivi, S. A1 - Hwang, S. J. A1 - Enroth, S. A1 - Kloiber, S. A1 - Trompet, S. A1 - Stengel, B. A1 - Hancock, S. J. A1 - Turner, S. T. A1 - Rosas, S. E. A1 - Stracke, S. A1 - Harris, T. B. A1 - Zeller, T. A1 - Zemunik, T. A1 - Lehtim?ki, T. A1 - Illig, T. A1 - Aspelund, T. A1 - Nikopensius, T. A1 - Esko, T. A1 - Tanaka, T. A1 - Gyllensten, U. A1 - V?lker, U. A1 - Emilsson, V. A1 - Vitart, V. A1 - Aalto, V. A1 - Gudnason, V. A1 - Chouraki, V. A1 - Chen, W. M. A1 - Igl, W. A1 - M?rz, W. A1 - Koenig, W. A1 - Lieb, W. A1 - Loos, R. J. A1 - Liu, Y. A1 - Snieder, H. A1 - Pramstaller, P. P. A1 - Parsa, A. A1 - O'Connell, J. R. A1 - Susztak, K. A1 - Hamet, P. A1 - Tremblay, J. A1 - De Boer, I. H. A1 - B?ger, C. A. A1 - Goessling, W. A1 - Chasman, D. I. A1 - K?ttgen, A. A1 - Kao, W. H. A1 - Fox, C. S. A1 - Abecasis, G. R. A1 - Adair, L. S. A1 - Alexander, M. A1 - Altshuler, D. A1 - Amin, N. A1 - Arking, D. E. A1 - Arora, P. A1 - Aulchenko, Y. A1 - Bakker, S. J. A1 - Bandinelli, S. A1 - Barroso, I. A1 - Beckmann, J. S. A1 - Beilby, J. P. A1 - Bergman, R. N. A1 - Bergmann, S. A1 - Bis, J. C. A1 - Boehnke, M. A1 - Bonnycastle, L. L. A1 - Bornstein, S. R. A1 - Bots, M. L. A1 - Bragg-Gresham, J. L. A1 - Brand, S. M. A1 - Brand, E. A1 - Braund, P. S. A1 - Brown, M. J. A1 - Burton, P. R. A1 - Casas, J. P. A1 - Caulfield, M. J. A1 - Chakravarti, A. A1 - Chambers, J. C. A1 - Chandak, G. R. A1 - Chang, Y. P. A1 - Charchar, F. J. A1 - Chaturvedi, N. A1 - Shin Cho, Y. A1 - Clarke, R. A1 - Collins, F. S. A1 - Collins, R. A1 - Connell, J. M. A1 - Cooper, J. A. A1 - Cooper, M. N. A1 - Cooper, R. S. A1 - Corsi, A. M. A1 - D?rr, M. A1 - Dahgam, S. A1 - Danesh, J. A1 - Davey Smith, G. A1 - Day, I. N. A1 - Deloukas, P. A1 - Denniff, M. A1 - Dominiczak, A. F. A1 - Dong, Y. A1 - Doumatey, A. A1 - Elliott, P. A1 - Elosua, R. A1 - Erdmann, J. A1 - Eyheramendy, S. A1 - Farrall, M. A1 - Fava, C. A1 - Forrester, T. A1 - Fowkes, F. G. A1 - Fox, E. R. A1 - Frayling, T. M. A1 - Galan, P. A1 - Ganesh, S. K. A1 - Garcia, M. A1 - Gaunt, T. R. A1 - Glazer, N. L. A1 - Go, M. J. A1 - Goel, A. A1 - Gr?ssler, J. A1 - Grobbee, D. E. A1 - Groop, L. A1 - Guarrera, S. A1 - Guo, X. A1 - Hadley, D. A1 - Hamsten, A. A1 - Han, B. G. A1 - Hardy, R. A1 - Hartikainen, A. L. A1 - Heath, S. A1 - Heckbert, S. R. A1 - Hedblad, B. A1 - Hercberg, S. A1 - Hernandez, D. A1 - Hicks, A. A. A1 - Hilton, G. A1 - Hingorani, A. D. A1 - Bolton, J. A. A1 - Hopewell, J. C. A1 - Howard, P. A1 - Humphries, S. E. A1 - Hunt, S. C. A1 - Hveem, K. A1 - Ikram, M. A. A1 - Islam, M. A1 - Iwai, N. A1 - Jarvelin, M. R. A1 - Jackson, A. U. A1 - Jafar, T. H. A1 - Janipalli, C. S. A1 - Johnson, T. A1 - Kathiresan, S. A1 - Khaw, K. T. A1 - Kim, H. L. A1 - Kinra, S. A1 - Kita, Y. A1 - Kivimaki, M. A1 - Kooner, J. S. A1 - Kumar, M. J. A1 - Kuh, D. A1 - Kulkarni, S. R. A1 - Kumari, M. A1 - Kuusisto, J. A1 - Kuznetsova, T. A1 - Laakso, M. A1 - Laan, M. A1 - Laitinen, J. A1 - Lakatta, E. G. A1 - Langefeld, C. D. A1 - Larson, M. G. A1 - Lathrop, M. A1 - Lawlor, D. A. A1 - Lawrence, R. W. A1 - Lee, J. Y. A1 - Lee, N. R. A1 - Levy, D. A1 - Li, Y. A1 - Longstreth, W. T. A1 - Luan, J. A1 - Lucas, G. A1 - Ludwig, B. A1 - Mangino, M. A1 - Mani, K. R. A1 - Marmot, M. G. A1 - Mattace-Raso, F. U. A1 - Matullo, G. A1 - McArdle, W. L. A1 - McKenzie, C. A. A1 - Meitinger, T. A1 - Melander, O. A1 - Meneton, P. A1 - Meschia, J. F. A1 - Miki, T. A1 - Milaneschi, Y. A1 - Mohlke, K. L. A1 - Mooser, V. A1 - Morken, M. A. A1 - Morris, R. W. A1 - Mosley, T. H. A1 - Najjar, S. A1 - Narisu, N. A1 - Newton-Cheh, C. A1 - Nguyen, K. D. A1 - Nilsson, P. A1 - Nyberg, F. A1 - O'Donnell, C. J. A1 - Ogihara, T. A1 - Ohkubo, T. A1 - Okamura, T. A1 - Ong, R. T. A1 - Ongen, H. A1 - Onland-Moret, N. C. A1 - O'Reilly, P. F. A1 - Org, E. A1 - Orru, M. A1 - Palmas, W. A1 - Palmen, J. A1 - Palmer, L. J. A1 - Palmer, N. D. A1 - Parker, A. N. A1 - Peden, J. F. A1 - Peltonen, L. A1 - Perola, M. A1 - Pihur, V. A1 - Platou, C. G. A1 - Plump, A. A1 - Prabhakaran, D. A1 - Psaty, B. M. A1 - Raffel, L. J. A1 - Rao, D. C. A1 - Rasheed, A. A1 - Ricceri, F. A1 - Rice, K. M. A1 - Rosengren, A. A1 - Rotter, J. I. A1 - Rudock, M. E. A1 - S?ber, S. A1 - Salako, T. A1 - Saleheen, D. A1 - Salomaa, V. A1 - Samani, N. J. A1 - Schwartz, S. M. A1 - Schwarz, P. E. A1 - Scott, L. J. A1 - Scott, J. A1 - Scuteri, A. A1 - Sehmi, J. S. A1 - Seielstad, M. A1 - Seshadri, S. A1 - Sharma, P. A1 - Shaw-Hawkins, S. A1 - Shi, G. A1 - Shrine, N. R. A1 - Sijbrands, E. J. A1 - Sim, X. A1 - Singleton, A. A1 - Sj?gren, M. A1 - Smith, N. L. A1 - Soler Artigas, M. A1 - Spector, T. D. A1 - Staessen, J. A. A1 - Stancakova, A. A1 - Steinle, N. I. A1 - Strachan, D. P. A1 - Stringham, H. M. A1 - Sun, Y. V. A1 - Swift, A. J. A1 - Tabara, Y. A1 - Tai, E. S. A1 - Talmud, P. J. A1 - Taylor, A. A1 - Terzic, J. A1 - Thelle, D. S. A1 - Tobin, M. D. A1 - Tomaszewski, M. A1 - Tripathy, V. A1 - Tuomilehto, J. A1 - Tzoulaki, I. A1 - Uda, M. A1 - Ueshima, H. A1 - Uiterwaal, C. S. A1 - Umemura, S. A1 - van der Harst, P. A1 - van der Schouw, Y. T. A1 - van Gilst, W. H. A1 - Vartiainen, E. A1 - Vasan, R. S. A1 - Veldre, G. A1 - Verwoert, G. C. A1 - Viigimaa, M. A1 - Vinay, D. G. A1 - Vineis, P. A1 - Voight, B. F. A1 - Vollenweider, P. A1 - Wagenknecht, L. E. A1 - Wain, L. V. A1 - Wang, X. A1 - Wang, T. J. A1 - Wareham, N. J. A1 - Watkins, H. A1 - Weder, A. B. A1 - Whincup, P. H. A1 - Wiggins, K. L. A1 - Witteman, J. C. A1 - Wong, A. A1 - Wu, Y. A1 - Yajnik, C. S. A1 - Yao, J. A1 - Young, J. H. A1 - Zelenika, D. A1 - Zhai, G. A1 - Zhang, W. A1 - Zhang, F. A1 - Zhao, J. H. A1 - Zhu, H. A1 - Zhu, X. A1 - Zitting, P. A1 - Zukowska-Szczechowska, E. A1 - Okada, Y. A1 - Wu, J. Y. A1 - Gu, D. A1 - Takeuchi, F. A1 - Takahashi, A. A1 - Maeda, S. A1 - Tsunoda, T. A1 - Chen, P. A1 - Lim, S. C. A1 - Wong, T. Y. A1 - Liu, J. A1 - Young, T. L. A1 - Aung, T. A1 - Teo, Y. Y. A1 - Kim, Y. J. A1 - Kang, D. A1 - Chen, C. H. A1 - Tsai, F. J. A1 - Chang, L. C. A1 - Fann, S. J. A1 - Mei, H. A1 - Hixson, J. E. A1 - Chen, S. A1 - Katsuya, T. A1 - Isono, M. A1 - Albrecht, E. A1 - Yamamoto, K. A1 - Kubo, M. A1 - Nakamura, Y. A1 - Kamatani, N. A1 - Kato, N. A1 - He, J. A1 - Chen, Y. T. A1 - Tanaka, T. A1 - Reilly, M. P. A1 - Schunkert, H. A1 - Assimes, T. L. A1 - Hall, A. A1 - Hengstenberg, C. A1 - K?nig, I. R. A1 - Laaksonen, R. A1 - McPherson, R. A1 - Thompson, J. R. A1 - Thorsteinsdottir, U. A1 - Ziegler, A. A1 - Absher, D. A1 - Chen, L. A1 - Cupples, L. A. A1 - Halperin, E. A1 - Li, M. A1 - Musunuru, K. A1 - Preuss, M. A1 - Schillert, A. A1 - Thorleifsson, G. A1 - Wells, G. A. A1 - Holm, H. A1 - Roberts, R. A1 - Stewart, A. F. A1 - Fortmann, S. A1 - Go, A. A1 - Hlatky, M. A1 - Iribarren, C. A1 - Knowles, J. A1 - Myers, R. A1 - Quertermous, T. A1 - Sidney, S. A1 - Risch, N. A1 - Tang, H. A1 - Blankenberg, S. A1 - Schnabel, R. A1 - Sinning, C. A1 - Lackner, K. J. A1 - Tiret, L. A1 - Nicaud, V. A1 - Cambien, F. A1 - Bickel, C. A1 - Rupprecht, H. J. A1 - Perret, C. A1 - Proust, C. A1 - M?nzel, T. F. A1 - Barbalic, M. A1 - Chen, I. Y. A1 - Demissie-Banjaw, S. A1 - Folsom, A. A1 - Lumley, T. A1 - Marciante, K. A1 - Taylor, K. D. A1 - Volcik, K. A1 - Gretarsdottir, S. A1 - Gulcher, J. R. A1 - Kong, A. A1 - Stefansson, K. A1 - Thorgeirsson, G. A1 - Andersen, K. A1 - Fischer, M. A1 - Grosshennig, A. A1 - Linsel-Nitschke, P. A1 - Stark, K. A1 - Schreiber, S. A1 - Aherrahrou, Z. A1 - Bruse, P. A1 - Doering, A. A1 - Klopp, N. A1 - Diemert, P. A1 - Loley, C. A1 - Medack, A. A1 - Nahrstedt, J. A1 - Peters, A. A1 - Wagner, A. K. A1 - Willenborg, C. A1 - B?hm, B. O. A1 - Dobnig, H. A1 - Grammer, T. B. A1 - Hoffmann, M. M. A1 - Meinitzer, A. A1 - Winkelmann, B. R. A1 - Pilz, S. A1 - Renner, W. A1 - Scharnagl, H. A1 - Stojakovic, T. A1 - Tomaschitz, A. A1 - Winkler, K. A1 - Guiducci, C. A1 - Burtt, N. A1 - Gabriel, S. B. A1 - Dandona, S. A1 - Jarinova, O. A1 - Qu, L. A1 - Wilensky, R. A1 - Matthai, W. A1 - Hakonarson, H. H. A1 - Devaney, J. A1 - Burnett, M. S. A1 - Pichard, A. D. A1 - Kent, K. M. A1 - Satler, L. A1 - Lindsay, J. M. A1 - Waksman, R. A1 - Knouff, C. W. A1 - Waterworth, D. M. A1 - Walker, M. C. A1 - Epstein, S. E. A1 - Rader, D. J. A1 - Nelson, C. P. A1 - Wright, B. J. A1 - Balmforth, A. J. A1 - Ball, S. G. A1 - Loehr, L. R. A1 - Rosamond, W. D. A1 - Benjamin, E. A1 - Haritunians, T. A1 - Couper, D. A1 - Murabito, J. A1 - Wang, Y. A. A1 - Stricker, B. H. A1 - Chang, P. P. A1 - Willerson, J. T. A1 - Felix, S. B. A1 - Watzinger, N. A1 - Aragam, J. A1 - Zweiker, R. A1 - Lind, L. A1 - Rodeheffer, R. J. A1 - Greiser, K. H. A1 - Deckers, J. W. A1 - Stritzke, J. A1 - Ingelsson, E. A1 - Kullo, I. A1 - Haerting, J. A1 - Reffelmann, T. A1 - Redfield, M. M. A1 - Werdan, K. A1 - Mitchell, G. F. A1 - Arnett, D. K. A1 - Gottdiener, J. S. A1 - Blettner, M. A1 - Friedrich, N. AB - Reduced 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. VL - 7 ER - TY - JOUR T1 - Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals. JF - JAMA Cardiol Y1 - 2016 A1 - Roberts, Jason D A1 - Hu, Donglei A1 - Heckbert, Susan R A1 - Alonso, Alvaro A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Olgin, Jeffrey E A1 - Magnani, Jared W A1 - Huntsman, Scott A1 - Burchard, Esteban G A1 - Arking, Dan E A1 - Bibbins-Domingo, Kirsten A1 - Harris, Tamara B A1 - Perez, Marco V A1 - Ziv, Elad A1 - Marcus, Gregory M AB -

IMPORTANCE: 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.

VL - 1 IS - 4 ER - TY - JOUR T1 - Genetic Variants Associated with Circulating Parathyroid Hormone. JF - J Am Soc Nephrol Y1 - 2016 A1 - Robinson-Cohen, Cassianne A1 - Lutsey, Pamela L A1 - Kleber, Marcus E A1 - Nielson, Carrie M A1 - Mitchell, Braxton D A1 - Bis, Joshua C A1 - Eny, Karen M A1 - Portas, Laura A1 - Eriksson, Joel A1 - Lorentzon, Mattias A1 - Koller, Daniel L A1 - Milaneschi, Yuri A1 - Teumer, Alexander A1 - Pilz, Stefan A1 - Nethander, Maria A1 - Selvin, Elizabeth A1 - Tang, Weihong A1 - Weng, Lu-Chen A1 - Wong, Hoi Suen A1 - Lai, Dongbing A1 - Peacock, Munro A1 - Hannemann, Anke A1 - Völker, Uwe A1 - Homuth, Georg A1 - Nauk, Matthias A1 - Murgia, Federico A1 - Pattee, Jack W A1 - Orwoll, Eric A1 - Zmuda, Joseph M A1 - Riancho, Jose Antonio A1 - Wolf, Myles A1 - Williams, Frances A1 - Penninx, Brenda A1 - Econs, Michael J A1 - Ryan, Kathleen A A1 - Ohlsson, Claes A1 - Paterson, Andrew D A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Rotter, Jerome I A1 - Pirastu, Mario A1 - Streeten, Elizabeth A1 - März, Winfried A1 - Fox, Caroline A1 - Coresh, Josef A1 - Wallaschofski, Henri A1 - Pankow, James S A1 - de Boer, Ian H A1 - Kestenbaum, Bryan AB -

Parathyroid 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.

ER - TY - JOUR T1 - Genetic variants in RBFOX3 are associated with sleep latency. JF - Eur J Hum Genet Y1 - 2016 A1 - Amin, Najaf A1 - Allebrandt, Karla V A1 - van der Spek, Ashley A1 - Müller-Myhsok, Bertram A1 - Hek, Karin A1 - Teder-Laving, Maris A1 - Hayward, Caroline A1 - Esko, Tõnu A1 - van Mill, Josine G A1 - Mbarek, Hamdi A1 - Watson, Nathaniel F A1 - Melville, Scott A A1 - Del Greco, Fabiola M A1 - Byrne, Enda M A1 - Oole, Edwin A1 - Kolcic, Ivana A1 - Chen, Ting-Hsu A1 - Evans, Daniel S A1 - Coresh, Josef A1 - Vogelzangs, Nicole A1 - Karjalainen, Juha A1 - Willemsen, Gonneke A1 - Gharib, Sina A A1 - Zgaga, Lina A1 - Mihailov, Evelin A1 - Stone, Katie L A1 - Campbell, Harry A1 - Brouwer, Rutger Ww A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Dogas, Zoran A1 - Marciante, Kristin D A1 - Campbell, Susan A1 - Borovecki, Fran A1 - Luik, Annemarie I A1 - Li, Man A1 - Hottenga, Jouke Jan A1 - Huffman, Jennifer E A1 - van den Hout, Mirjam Cgn A1 - Cummings, Steven R A1 - Aulchenko, Yurii S A1 - Gehrman, Philip R A1 - Uitterlinden, André G A1 - Wichmann, Heinz-Erich A1 - Müller-Nurasyid, Martina A1 - Fehrmann, Rudolf Sn A1 - Montgomery, Grant W A1 - Hofman, Albert A1 - Kao, Wen Hong Linda A1 - Oostra, Ben A A1 - Wright, Alan F A1 - Vink, Jacqueline M A1 - Wilson, James F A1 - Pramstaller, Peter P A1 - Hicks, Andrew A A1 - Polasek, Ozren A1 - Punjabi, Naresh M A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Heath, Andrew C A1 - Merrow, Martha A1 - Tranah, Gregory J A1 - Gottlieb, Daniel J A1 - Boomsma, Dorret I A1 - Martin, Nicholas G A1 - Rudan, Igor A1 - Tiemeier, Henning A1 - van IJcken, Wilfred Fj A1 - Penninx, Brenda W A1 - Metspalu, Andres A1 - Meitinger, Thomas A1 - Franke, Lude A1 - Roenneberg, Till A1 - van Duijn, Cornelia M AB -

Time 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.

VL - 24 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27142678?dopt=Abstract ER - TY - JOUR T1 - {The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals JF - Nat Genet Y1 - 2016 A1 - Ehret, G. B. A1 - Ferreira, T. A1 - Chasman, D. I. A1 - Jackson, A. U. A1 - Schmidt, E. M. A1 - Johnson, T. A1 - Thorleifsson, G. A1 - Luan, J. A1 - Donnelly, L. A. A1 - Kanoni, S. A1 - Petersen, A. K. A1 - Pihur, V. A1 - Strawbridge, R. J. A1 - Shungin, D. A1 - Hughes, M. F. A1 - Meirelles, O. A1 - Kaakinen, M. A1 - Bouatia-Naji, N. A1 - Kristiansson, K. A1 - Shah, S. A1 - Kleber, M. E. A1 - Guo, X. A1 - Lyytik?inen, L. P. A1 - Fava, C. A1 - Eriksson, N. A1 - Nolte, I. M. A1 - Magnusson, P. K. A1 - Salfati, E. L. A1 - Rallidis, L. S. A1 - Theusch, E. A1 - Smith, A. J. P. A1 - Folkersen, L. A1 - Witkowska, K. A1 - Pers, T. H. A1 - Joehanes, R. A1 - Kim, S. K. A1 - Lataniotis, L. A1 - Jansen, R. A1 - Johnson, A. D. A1 - Warren, H. A1 - Kim, Y. J. A1 - Zhao, W. A1 - Wu, Y. A1 - Tayo, B. O. A1 - Bochud, M. A1 - Absher, D. A1 - Adair, L. S. A1 - Amin, N. A1 - Arking, D. E. A1 - Axelsson, T. A1 - Baldassarre, D. A1 - Balkau, B. A1 - Bandinelli, S. A1 - Barnes, M. R. A1 - Barroso, I. A1 - Bevan, S. A1 - Bis, J. C. A1 - Bjornsdottir, G. A1 - Boehnke, M. A1 - Boerwinkle, E. A1 - Bonnycastle, L. L. A1 - Boomsma, D. I. A1 - Bornstein, S. R. A1 - Brown, M. J. A1 - Burnier, M. A1 - Cabrera, C. P. A1 - Chambers, J. C. A1 - Chang, I. S. A1 - Cheng, C. Y. A1 - Chines, P. S. A1 - Chung, R. H. A1 - Collins, F. S. A1 - Connell, J. M. A1 - D?ring, A. A1 - Dallongeville, J. A1 - Danesh, J. A1 - de Faire, U. A1 - Delgado, G. A1 - Dominiczak, A. F. A1 - Doney, A. S. F. A1 - Drenos, F. A1 - Edkins, S. A1 - Eicher, J. D. A1 - Elosua, R. A1 - Enroth, S. A1 - Erdmann, J. A1 - Eriksson, P. A1 - Esko, T. A1 - Evangelou, E. A1 - Evans, A. A1 - Fall, T. A1 - Farrall, M. A1 - Felix, J. F. A1 - Ferri?res, J. A1 - Ferrucci, L. A1 - Fornage, M. A1 - Forrester, T. A1 - Franceschini, N. A1 - Duran, O. H. F. A1 - Franco-Cereceda, A. A1 - Fraser, R. M. A1 - Ganesh, S. K. A1 - Gao, H. A1 - Gertow, K. A1 - Gianfagna, F. A1 - Gigante, B. A1 - Giulianini, F. A1 - Goel, A. A1 - Goodall, A. H. A1 - Goodarzi, M. O. A1 - Gorski, M. A1 - Gr??ler, J. A1 - Groves, C. A1 - Gudnason, V. A1 - Gyllensten, U. A1 - Hallmans, G. A1 - Hartikainen, A. L. A1 - Hassinen, M. A1 - Havulinna, A. S. A1 - Hayward, C. A1 - Hercberg, S. A1 - Herzig, K. H. A1 - Hicks, A. A. A1 - Hingorani, A. D. A1 - Hirschhorn, J. N. A1 - Hofman, A. A1 - Holmen, J. A1 - Holmen, O. L. A1 - Hottenga, J. J. A1 - Howard, P. A1 - Hsiung, C. A. A1 - Hunt, S. C. A1 - Ikram, M. A. A1 - Illig, T. A1 - Iribarren, C. A1 - Jensen, R. A. A1 - K?h?nen, M. A1 - Kang, H. A1 - Kathiresan, S. A1 - Keating, B. J. A1 - Khaw, K. T. A1 - Kim, Y. K. A1 - Kim, E. A1 - Kivimaki, M. A1 - Klopp, N. A1 - Kolovou, G. A1 - Komulainen, P. A1 - Kooner, J. S. A1 - Kosova, G. A1 - Krauss, R. M. A1 - Kuh, D. A1 - Kutalik, Z. A1 - Kuusisto, J. A1 - Kval?y, K. A1 - Lakka, T. A. A1 - Lee, N. R. A1 - Lee, I. T. A1 - Lee, W. J. A1 - Levy, D. A1 - Li, X. A1 - Liang, K. W. A1 - Lin, H. A1 - Lin, L. A1 - Lindstr?m, J. A1 - Lobbens, S. A1 - M?nnist?, S. A1 - M?ller, G. A1 - M?ller-Nurasyid, M. A1 - Mach, F. A1 - Markus, H. S. A1 - Marouli, E. A1 - McCarthy, M. I. A1 - McKenzie, C. A. A1 - Meneton, P. A1 - Menni, C. A1 - Metspalu, A. A1 - Mijatovic, V. A1 - Moilanen, L. A1 - Montasser, M. E. A1 - Morris, A. D. A1 - Morrison, A. C. A1 - Mulas, A. A1 - Nagaraja, R. A1 - Narisu, N. A1 - Nikus, K. A1 - O'Donnell, C. J. A1 - O'Reilly, P. F. A1 - Ong, K. K. A1 - Paccaud, F. A1 - Palmer, C. D. A1 - Parsa, A. A1 - Pedersen, N. L. A1 - Penninx, B. W. A1 - Perola, M. A1 - Peters, A. A1 - Poulter, N. A1 - Pramstaller, P. P. A1 - Psaty, B. M. A1 - Quertermous, T. A1 - Rao, D. C. A1 - Rasheed, A. A1 - Rayner, N. W. N. W. R. A1 - Renstr?m, F. A1 - Rettig, R. A1 - Rice, K. M. A1 - Roberts, R. A1 - Rose, L. M. A1 - Rossouw, J. A1 - Samani, N. J. A1 - Sanna, S. A1 - Saramies, J. A1 - Schunkert, H. A1 - Sebert, S. A1 - Sheu, W. H. A1 - Shin, Y. A. A1 - Sim, X. A1 - Smit, J. H. A1 - Smith, A. V. A1 - Sosa, M. X. A1 - Spector, T. D. A1 - Stan??kov?, A. A1 - Stanton, A. A1 - Stirrups, K. E. A1 - Stringham, H. M. A1 - Sundstrom, J. A1 - Swift, A. J. A1 - Syv?nen, A. C. A1 - Tai, E. S. A1 - Tanaka, T. A1 - Tarasov, K. V. A1 - Teumer, A. A1 - Thorsteinsdottir, U. A1 - Tobin, M. D. A1 - Tremoli, E. A1 - Uitterlinden, A. G. A1 - Uusitupa, M. A1 - Vaez, A. A1 - Vaidya, D. A1 - van Duijn, C. M. A1 - van Iperen, E. P. A. A1 - Vasan, R. S. A1 - Verwoert, G. C. A1 - Virtamo, J. A1 - Vitart, V. A1 - Voight, B. F. A1 - Vollenweider, P. A1 - Wagner, A. A1 - Wain, L. V. A1 - Wareham, N. J. A1 - Watkins, H. A1 - Weder, A. B. A1 - Westra, H. J. A1 - Wilks, R. A1 - Wilsgaard, T. A1 - Wilson, J. F. A1 - Wong, T. Y. A1 - Yang, T. P. A1 - Yao, J. A1 - Yengo, L. A1 - Zhang, W. A1 - Zhao, J. H. A1 - Zhu, X. A1 - Bovet, P. A1 - Cooper, R. S. A1 - Mohlke, K. L. A1 - Saleheen, D. A1 - Lee, J. Y. A1 - Elliott, P. A1 - Gierman, H. J. A1 - Willer, C. J. A1 - Franke, L. A1 - Hovingh, G. K. A1 - Taylor, K. D. A1 - Dedoussis, G. A1 - Sever, P. A1 - Wong, A. A1 - Lind, L. A1 - Assimes, T. L. A1 - Nj?lstad, I. A1 - Schwarz, P. E. A1 - Langenberg, C. A1 - Snieder, H. A1 - Caulfield, M. J. A1 - Melander, O. A1 - Laakso, M. A1 - Saltevo, J. A1 - Rauramaa, R. A1 - Tuomilehto, J. A1 - Ingelsson, E. A1 - Lehtim?ki, T. A1 - Hveem, K. A1 - Palmas, W. A1 - M?rz, W. A1 - Kumari, M. A1 - Salomaa, V. A1 - Chen, Y. I. A1 - Rotter, J. I. A1 - Froguel, P. A1 - Jarvelin, M. R. A1 - Lakatta, E. G. A1 - Kuulasmaa, K. A1 - Franks, P. W. A1 - Hamsten, A. A1 - Wichmann, H. E. A1 - Palmer, C. N. A. A1 - Stefansson, K. A1 - Ridker, P. M. A1 - Loos, R. J. F. A1 - Chakravarti, A. A1 - Deloukas, P. A1 - Morris, A. P. A1 - Newton-Cheh, C. A1 - Munroe, P. B. AB - To 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. VL - 48 ER - TY - JOUR T1 - Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. JF - Stroke Y1 - 2016 A1 - Cheng, Yu-Ching A1 - Stanne, Tara M A1 - Giese, Anne-Katrin A1 - Ho, Weang Kee A1 - Traylor, Matthew A1 - Amouyel, Philippe A1 - Holliday, Elizabeth G A1 - Malik, Rainer A1 - Xu, Huichun A1 - Kittner, Steven J A1 - Cole, John W A1 - O'Connell, Jeffrey R A1 - Danesh, John A1 - Rasheed, Asif A1 - Zhao, Wei A1 - Engelter, Stefan A1 - Grond-Ginsbach, Caspar A1 - Kamatani, Yoichiro A1 - Lathrop, Mark A1 - Leys, Didier A1 - Thijs, Vincent A1 - Metso, Tiina M A1 - Tatlisumak, Turgut A1 - Pezzini, Alessandro A1 - Parati, Eugenio A A1 - Norrving, Bo A1 - Bevan, Steve A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Slowik, Agnieszka A1 - Lindgren, Arne A1 - Walters, Matthew R A1 - Jannes, Jim A1 - Shen, Jess A1 - Crosslin, David A1 - Doheny, Kimberly A1 - Laurie, Cathy C A1 - Kanse, Sandip M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Mosley, Thomas H A1 - Hopewell, Jemma C A1 - Strauch, Konstantin A1 - Müller-Nurasyid, Martina A1 - Gieger, Christian A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Meisinger, Christine A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Meschia, James F A1 - Seshadri, Sudha A1 - Sharma, Pankaj A1 - Worrall, Bradford A1 - Jern, Christina A1 - Levi, Christopher A1 - Dichgans, Martin A1 - Boncoraglio, Giorgio B A1 - Markus, Hugh S A1 - Debette, Stephanie A1 - Rolfs, Arndt A1 - Saleheen, Danish A1 - Mitchell, Braxton D KW - Adult KW - African Continental Ancestry Group KW - Age of Onset KW - Aged KW - Asian Continental Ancestry Group KW - Brain Ischemia KW - Chromosomes, Human, Pair 10 KW - Computer Simulation KW - DNA, Intergenic KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Serine Endopeptidases KW - Stroke AB -

BACKGROUND 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.

VL - 47 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract ER - TY - JOUR T1 - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. JF - PLoS One Y1 - 2016 A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - White, Charles C A1 - Smith, Albert Vernon A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Trompet, Stella A1 - Chasman, Daniel I A1 - Lumley, Thomas A1 - Völker, Uwe A1 - Buckley, Brendan M A1 - Ding, Jingzhong A1 - Jensen, Majken K A1 - Folsom, Aaron R A1 - Kritchevsky, Stephen B A1 - Girman, Cynthia J A1 - Ford, Ian A1 - Dörr, Marcus A1 - Salomaa, Veikko A1 - Uitterlinden, André G A1 - Eiriksdottir, Gudny A1 - Vasan, Ramachandran S A1 - Franceschini, Nora A1 - Carty, Cara L A1 - Virtamo, Jarmo A1 - Demissie, Serkalem A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Heckbert, Susan R A1 - Ferrieres, Jean A1 - Ducimetiere, Pierre A1 - Smith, Nicholas L A1 - Wang, Ying A A1 - Siscovick, David S A1 - Rice, Kenneth M A1 - Wiklund, Per-Gunnar A1 - Taylor, Kent D A1 - Evans, Alun A1 - Kee, Frank A1 - Rotter, Jerome I A1 - Karvanen, Juha A1 - Kuulasmaa, Kari A1 - Heiss, Gerardo A1 - Kraft, Peter A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Markus, Marcello R P A1 - Rose, Lynda M A1 - Silander, Kaisa A1 - Wagner, Peter A1 - Benjamin, Emelia J A1 - Lohman, Kurt A1 - Stott, David J A1 - Rivadeneira, Fernando A1 - Harris, Tamara B A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Rimm, Eric B A1 - Jukema, J Wouter A1 - Völzke, Henry A1 - Ridker, Paul M A1 - Blankenberg, Stefan A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Aged KW - Cohort Studies KW - Cooperative Behavior KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: 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.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. JF - Bone Rep Y1 - 2016 A1 - Taylor, Kira C A1 - Evans, Daniel S A1 - Edwards, Digna R Velez A1 - Edwards, Todd L A1 - Sofer, Tamar A1 - Li, Guo A1 - Liu, Youfang A1 - Franceschini, Nora A1 - Jackson, Rebecca D A1 - Giri, Ayush A1 - Donneyong, Macarius A1 - Psaty, Bruce A1 - Rotter, Jerome I A1 - LaCroix, Andrea Z A1 - Jordan, Joanne M A1 - Robbins, John A A1 - Lewis, Beth A1 - Stefanick, Marcia L A1 - Liu, Yongmei A1 - Garcia, Melissa A1 - Harris, Tamara A1 - Cauley, Jane A A1 - North, Kari E AB -

BACKGROUND: 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.

VL - 5 ER - TY - JOUR T1 - Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. JF - Diabetes Y1 - 2016 A1 - Walford, Geoffrey A A1 - Gustafsson, Stefan A1 - Rybin, Denis A1 - Stančáková, Alena A1 - Chen, Han A1 - Liu, Ching-Ti A1 - Hong, Jaeyoung A1 - Jensen, Richard A A1 - Rice, Ken A1 - Morris, Andrew P A1 - Mägi, Reedik A1 - Tönjes, Anke A1 - Prokopenko, Inga A1 - Kleber, Marcus E A1 - Delgado, Graciela A1 - Silbernagel, Günther A1 - Jackson, Anne U A1 - Appel, Emil V A1 - Grarup, Niels A1 - Lewis, Joshua P A1 - Montasser, May E A1 - Landenvall, Claes A1 - Staiger, Harald A1 - Luan, Jian'an A1 - Frayling, Timothy M A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Morcillo, Sonsoles A1 - Martínez-Larrad, María Teresa A1 - Biggs, Mary L A1 - Chen, Yii-Der Ida A1 - Corbaton-Anchuelo, Arturo A1 - Færch, Kristine A1 - Gómez-Zumaquero, Juan Miguel A1 - Goodarzi, Mark O A1 - Kizer, Jorge R A1 - Koistinen, Heikki A A1 - Leong, Aaron A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Machicao, Fausto A1 - Manning, Alisa K A1 - Martín-Núñez, Gracia María A1 - Rojo-Martínez, Gemma A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Zmuda, Joseph M A1 - Zhang, Zhongyang A1 - Serrano-Ríos, Manuel A1 - Smith, Ulf A1 - Soriguer, Federico A1 - Hansen, Torben A1 - Jørgensen, Torben J A1 - Linnenberg, Allan A1 - Pedersen, Oluf A1 - Walker, Mark A1 - Langenberg, Claudia A1 - Scott, Robert A A1 - Wareham, Nicholas J A1 - Fritsche, Andreas A1 - Häring, Hans-Ulrich A1 - Stefan, Norbert A1 - Groop, Leif A1 - O'Connell, Jeff R A1 - Boehnke, Michael A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - März, Winfried A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Psaty, Bruce M A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Meigs, James B A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Florez, Jose C AB -

Genome-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.

VL - 65 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27416945?dopt=Abstract ER - TY - JOUR T1 - Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. JF - Aging Cell Y1 - 2016 A1 - Teumer, Alexander A1 - Qi, Qibin A1 - Nethander, Maria A1 - Aschard, Hugues A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Berndt, Sonja I A1 - Bidlingmaier, Martin A1 - Broer, Linda A1 - Cappola, Anne A1 - Ceda, Gian Paolo A1 - Chanock, Stephen A1 - Chen, Ming-Huei A1 - Chen, Tai C A1 - Chen, Yii-Der Ida A1 - Chung, Jonathan A1 - Del Greco Miglianico, Fabiola A1 - Eriksson, Joel A1 - Ferrucci, Luigi A1 - Friedrich, Nele A1 - Gnewuch, Carsten A1 - Goodarzi, Mark O A1 - Grarup, Niels A1 - Guo, Tingwei A1 - Hammer, Elke A1 - Hayes, Richard B A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Houwing-Duistermaat, Jeanine J A1 - Hu, Frank A1 - Hunter, David J A1 - Husemoen, Lise L A1 - Isaacs, Aaron A1 - Jacobs, Kevin B A1 - Janssen, Joop A M J L A1 - Jansson, John-Olov A1 - Jehmlich, Nico A1 - Johnson, Simon A1 - Juul, Anders A1 - Karlsson, Magnus A1 - Kilpeläinen, Tuomas O A1 - Kovacs, Peter A1 - Kraft, Peter A1 - Li, Chao A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Lu, Yingchang A1 - Maggio, Marcello A1 - Mägi, Reedik A1 - Meigs, James A1 - Mellström, Dan A1 - Nauck, Matthias A1 - Newman, Anne B A1 - Pollak, Michael N A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Psaty, Bruce M A1 - Reincke, Martin A1 - Rimm, Eric B A1 - Rotter, Jerome I A1 - Saint Pierre, Aude A1 - Schurmann, Claudia A1 - Seshadri, Sudha A1 - Sjögren, Klara A1 - Slagboom, P Eline A1 - Strickler, Howard D A1 - Stumvoll, Michael A1 - Suh, Yousin A1 - Sun, Qi A1 - Zhang, Cuilin A1 - Svensson, Johan A1 - Tanaka, Toshiko A1 - Tare, Archana A1 - Tönjes, Anke A1 - Uh, Hae-Won A1 - van Duijn, Cornelia M A1 - van Heemst, Diana A1 - Vandenput, Liesbeth A1 - Vasan, Ramachandran S A1 - Völker, Uwe A1 - Willems, Sara M A1 - Ohlsson, Claes A1 - Wallaschofski, Henri A1 - Kaplan, Robert C AB -

The 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.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27329260?dopt=Abstract ER - TY - JOUR T1 - Global 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. JF - Circulation Y1 - 2016 A1 - Waks, Jonathan W A1 - Sitlani, Colleen M A1 - Soliman, Elsayed Z A1 - Kabir, Muammar A1 - Ghafoori, Elyar A1 - Biggs, Mary L A1 - Henrikson, Charles A A1 - Sotoodehnia, Nona A1 - Biering-Sørensen, Tor A1 - Agarwal, Sunil K A1 - Siscovick, David S A1 - Post, Wendy S A1 - Solomon, Scott D A1 - Buxton, Alfred E A1 - Josephson, Mark E A1 - Tereshchenko, Larisa G AB -

BACKGROUND: 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.

VL - 133 IS - 23 ER - TY - JOUR T1 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Matteini, Amy M A1 - Tanaka, Toshiko A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - Eicher, John D A1 - Johnson, Andrew D A1 - Arnold, Alice M A1 - Callisaya, Michele L A1 - Davies, Gail A1 - Evans, Daniel S A1 - Holtfreter, Birte A1 - Lohman, Kurt A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Yu, Lei A1 - Arking, Dan E A1 - Buchman, Aron S A1 - Chibinik, Lori B A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Faul, Jessica D A1 - Garcia, Melissa E A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - Liewald, David C A1 - Liu, Yongmei A1 - Lopez, Lorna A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - Starr, John M A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Weir, David R A1 - Yaffe, Kristine A1 - Zhao, Wei A1 - Zhuang, Wei Vivian A1 - Zmuda, Joseph M A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Kocher, Thomas A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Spector, Timothy D A1 - Srikanth, Velandai K A1 - Windham, B Gwen A1 - Zillikens, M Carola A1 - Newman, Anne B A1 - Walston, Jeremy D A1 - Kiel, Douglas P A1 - Murabito, Joanne M AB -

Decline 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.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - GWAS for executive function and processing speed suggests involvement of the CADM2 gene. JF - Mol Psychiatry Y1 - 2016 A1 - Ibrahim-Verbaas, C A A1 - Bressler, J A1 - Debette, S A1 - Schuur, M A1 - Smith, A V A1 - Bis, J C A1 - Davies, G A1 - Trompet, S A1 - Smith, J A A1 - Wolf, C A1 - Chibnik, L B A1 - Liu, Y A1 - Vitart, V A1 - Kirin, M A1 - Petrovic, K A1 - Polasek, O A1 - Zgaga, L A1 - Fawns-Ritchie, C A1 - Hoffmann, P A1 - Karjalainen, J A1 - Lahti, J A1 - Llewellyn, D J A1 - Schmidt, C O A1 - Mather, K A A1 - Chouraki, V A1 - Sun, Q A1 - Resnick, S M A1 - Rose, L M A1 - Oldmeadow, C A1 - Stewart, M A1 - Smith, B H A1 - Gudnason, V A1 - Yang, Q A1 - Mirza, S S A1 - Jukema, J W A1 - deJager, P L A1 - Harris, T B A1 - Liewald, D C A1 - Amin, N A1 - Coker, L H A1 - Stegle, O A1 - Lopez, O L A1 - Schmidt, R A1 - Teumer, A A1 - Ford, I A1 - Karbalai, N A1 - Becker, J T A1 - Jonsdottir, M K A1 - Au, R A1 - Fehrmann, R S N A1 - Herms, S A1 - Nalls, M A1 - Zhao, W A1 - Turner, S T A1 - Yaffe, K A1 - Lohman, K A1 - van Swieten, J C A1 - Kardia, S L R A1 - Knopman, D S A1 - Meeks, W M A1 - Heiss, G A1 - Holliday, E G A1 - Schofield, P W A1 - Tanaka, T A1 - Stott, D J A1 - Wang, J A1 - Ridker, P A1 - Gow, A J A1 - Pattie, A A1 - Starr, J M A1 - Hocking, L J A1 - Armstrong, N J A1 - McLachlan, S A1 - Shulman, J M A1 - Pilling, L C A1 - Eiriksdottir, G A1 - Scott, R J A1 - Kochan, N A A1 - Palotie, A A1 - Hsieh, Y-C A1 - Eriksson, J G A1 - Penman, A A1 - Gottesman, R F A1 - Oostra, B A A1 - Yu, L A1 - DeStefano, A L A1 - Beiser, A A1 - Garcia, M A1 - Rotter, J I A1 - Nöthen, M M A1 - Hofman, A A1 - Slagboom, P E A1 - Westendorp, R G J A1 - Buckley, B M A1 - Wolf, P A A1 - Uitterlinden, A G A1 - Psaty, B M A1 - Grabe, H J A1 - Bandinelli, S A1 - Chasman, D I A1 - Grodstein, F A1 - Räikkönen, K A1 - Lambert, J-C A1 - Porteous, D J A1 - Price, J F A1 - Sachdev, P S A1 - Ferrucci, L A1 - Attia, J R A1 - Rudan, I A1 - Hayward, C A1 - Wright, A F A1 - Wilson, J F A1 - Cichon, S A1 - Franke, L A1 - Schmidt, H A1 - Ding, J A1 - de Craen, A J M A1 - Fornage, M A1 - Bennett, D A A1 - Deary, I J A1 - Ikram, M A A1 - Launer, L J A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - van Duijn, C M A1 - Mosley, T H AB -

To 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.

VL - 21 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25869804?dopt=Abstract ER - TY - JOUR T1 - Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation. JF - Am Heart J Y1 - 2016 A1 - Roberts, Jason D A1 - Dewland, Thomas A A1 - Glidden, David V A1 - Hoffmann, Thomas J A1 - Arking, Dan E A1 - Chen, Lin Y A1 - Psaty, Bruce M A1 - Olgin, Jeffrey E A1 - Alonso, Alvaro A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: 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.

VL - 175 ER - TY - JOUR T1 - Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration. JF - Eur J Prev Cardiol Y1 - 2016 A1 - Willeit, Peter A1 - Thompson, Simon G A1 - Agewall, Stefan A1 - Bergström, Göran A1 - Bickel, Horst A1 - Catapano, Alberico L A1 - Chien, Kuo-Liong A1 - de Groot, Eric A1 - Empana, Jean-Philippe A1 - Etgen, Thorleif A1 - Franco, Oscar H A1 - Iglseder, Bernhard A1 - Johnsen, Stein H A1 - Kavousi, Maryam A1 - Lind, Lars A1 - Liu, Jing A1 - Mathiesen, Ellisiv B A1 - Norata, Giuseppe D A1 - Olsen, Michael H A1 - Papagianni, Aikaterini A1 - Poppert, Holger A1 - Price, Jackie F A1 - Sacco, Ralph L A1 - Yanez, David N A1 - Zhao, Dong A1 - Schminke, Ulf A1 - Bülbül, Alpaslan A1 - Polak, Joseph F A1 - Sitzer, Matthias A1 - Hofman, Albert A1 - Grigore, Liliana A1 - Dörr, Marcus A1 - Su, Ta-Chen A1 - Ducimetiere, Pierre A1 - Xie, Wuxiang A1 - Ronkainen, Kimmo A1 - Kiechl, Stefan A1 - Rundek, Tatjana A1 - Robertson, Christine A1 - Fagerberg, Björn A1 - Bokemark, Lena A1 - Steinmetz, Helmuth A1 - Ikram, M Arfan A1 - Völzke, Henry A1 - Lin, Hung-Ju A1 - Plichart, Matthieu A1 - Tuomainen, Tomi-Pekka A1 - Desvarieux, Moïse A1 - McLachlan, Stela A1 - Schmidt, Caroline A1 - Kauhanen, Jussi A1 - Willeit, Johann A1 - Lorenz, Matthias W A1 - Sander, Dirk AB -

BACKGROUND: 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.

VL - 23 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25416041?dopt=Abstract ER - TY - JOUR T1 - Insulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: CHS cohort. JF - J Clin Endocrinol Metab Y1 - 2016 A1 - Kaplan, Robert C A1 - Strizich, Garrett A1 - Aneke-Nash, Chino A1 - Dominguez-Islas, Clara A1 - Bůzková, Petra A1 - Strickler, Howard A1 - Rohan, Thomas A1 - Pollak, Michael A1 - Kuller, Lewis A1 - Kizer, Jorge R A1 - Cappola, Anne A1 - Li, Christopher I A1 - Psaty, Bruce M A1 - Newman, Anne AB -

CONTEXT: 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.

ER - TY - JOUR T1 - Interaction 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. JF - Am J Clin Nutr Y1 - 2016 A1 - Ma, Yiyi A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Manichaikul, Ani W A1 - Chu, Audrey Y A1 - Samieri, Cecilia A1 - Zhou, Xia A1 - Guan, Weihua A1 - Wang, Lu A1 - Biggs, Mary L A1 - Chen, Yii-der I A1 - Hernandez, Dena G A1 - Borecki, Ingrid A1 - Chasman, Daniel I A1 - Rich, Stephen S A1 - Ferrucci, Luigi A1 - Irvin, Marguerite Ryan A1 - Aslibekyan, Stella A1 - Zhi, Degui A1 - Tiwari, Hemant K A1 - Claas, Steven A A1 - Sha, Jin A1 - Kabagambe, Edmond K A1 - Lai, Chao-Qiang A1 - Parnell, Laurence D A1 - Lee, Yu-Chi A1 - Amouyel, Philippe A1 - Lambert, Jean-Charles A1 - Psaty, Bruce M A1 - King, Irena B A1 - Mozaffarian, Dariush A1 - McKnight, Barbara A1 - Bandinelli, Stefania A1 - Tsai, Michael Y A1 - Ridker, Paul M A1 - Ding, Jingzhong A1 - Mstat, Kurt Lohmant A1 - Liu, Yongmei A1 - Sotoodehnia, Nona A1 - Barberger-Gateau, Pascale A1 - Steffen, Lyn M A1 - Siscovick, David S A1 - Absher, Devin A1 - Arnett, Donna K A1 - Ordovas, Jose M A1 - Lemaitre, Rozenn N KW - Apolipoproteins E KW - ATP Binding Cassette Transporter 1 KW - Cholesterol, HDL KW - Cohort Studies KW - Diet KW - DNA Methylation KW - Eicosapentaenoic Acid KW - Epigenesis, Genetic KW - Fatty Acids KW - Gene Expression Regulation KW - Humans KW - Lipids KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic KW - Triglycerides AB -

BACKGROUND: 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.

VL - 103 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26791180?dopt=Abstract ER - TY - JOUR T1 - KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. JF - Proc Natl Acad Sci U S A Y1 - 2016 A1 - Schumann, Gunter A1 - Liu, Chunyu A1 - O'Reilly, Paul A1 - Gao, He A1 - Song, Parkyong A1 - Xu, Bing A1 - Ruggeri, Barbara A1 - Amin, Najaf A1 - Jia, Tianye A1 - Preis, Sarah A1 - Segura Lepe, Marcelo A1 - Akira, Shizuo A1 - Barbieri, Caterina A1 - Baumeister, Sebastian A1 - Cauchi, Stephane A1 - Clarke, Toni-Kim A1 - Enroth, Stefan A1 - Fischer, Krista A1 - Hällfors, Jenni A1 - Harris, Sarah E A1 - Hieber, Saskia A1 - Hofer, Edith A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Joshi, Peter K A1 - Kaartinen, Niina A1 - Laitinen, Jaana A1 - Lemaitre, Rozenn A1 - Loukola, Anu A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Mangino, Massimo A1 - Manichaikul, Ani A1 - Mbarek, Hamdi A1 - Milaneschi, Yuri A1 - Moayyeri, Alireza A1 - Mukamal, Kenneth A1 - Nelson, Christopher A1 - Nettleton, Jennifer A1 - Partinen, Eemil A1 - Rawal, Rajesh A1 - Robino, Antonietta A1 - Rose, Lynda A1 - Sala, Cinzia A1 - Satoh, Takashi A1 - Schmidt, Reinhold A1 - Schraut, Katharina A1 - Scott, Robert A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Uitterlinden, André G A1 - Venturini, Cristina A1 - Vergnaud, Anne-Claire A1 - Verweij, Niek A1 - Vitart, Veronique A1 - Vuckovic, Dragana A1 - Wedenoja, Juho A1 - Yengo, Loic A1 - Yu, Bing A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Boomsma, Dorret I A1 - Chambers, John A1 - Chasman, Daniel I A1 - Daniela, Toniolo A1 - de Geus, Eco A1 - Deary, Ian A1 - Eriksson, Johan G A1 - Esko, Tõnu A1 - Eulenburg, Volker A1 - Franco, Oscar H A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Heath, Andrew C A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Huth, Cornelia A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Kaprio, Jaakko A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Madden, Pamela A F A1 - Martin, Nicholas A1 - Morrison, Alanna A1 - Penninx, Brenda A1 - Pirastu, Nicola A1 - Psaty, Bruce A1 - Raitakari, Olli A1 - Ridker, Paul A1 - Rose, Richard A1 - Rotter, Jerome I A1 - Samani, Nilesh J A1 - Schmidt, Helena A1 - Spector, Tim D A1 - Stott, David A1 - Strachan, David A1 - Tzoulaki, Ioanna A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Marques-Vidal, Pedro A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wilson, James A1 - Wolffenbuttel, Bruce A1 - Bakalkin, Georgy A1 - Evangelou, Evangelos A1 - Liu, Yun A1 - Rice, Kenneth M A1 - Desrivières, Sylvane A1 - Kliewer, Steven A A1 - Mangelsdorf, David J A1 - Müller, Christian P A1 - Levy, Daniel A1 - Elliott, Paul AB -

Excessive 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.

VL - 113 IS - 50 ER - TY - JOUR T1 - Lack of association of plasma gamma prime (γ') fibrinogen with incident cardiovascular disease. JF - Thromb Res Y1 - 2016 A1 - Appiah, Duke A1 - Heckbert, Susan R A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Folsom, Aaron R AB -

INTRODUCTION: 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.

VL - 143 ER - TY - JOUR T1 - Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. JF - Am J Hum Genet Y1 - 2016 A1 - Tajuddin, Salman M A1 - Schick, Ursula M A1 - Eicher, John D A1 - Chami, Nathalie A1 - Giri, Ayush A1 - Brody, Jennifer A A1 - Hill, W David A1 - Kacprowski, Tim A1 - Li, Jin A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Mihailov, Evelin A1 - O'Donoghue, Michelle L A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Polfus, Linda M A1 - Smith, Albert Vernon A1 - Schurmann, Claudia A1 - Vacchi-Suzzi, Caterina A1 - Waterworth, Dawn M A1 - Evangelou, Evangelos A1 - Yanek, Lisa R A1 - Burt, Amber A1 - Chen, Ming-Huei A1 - van Rooij, Frank J A A1 - Floyd, James S A1 - Greinacher, Andreas A1 - Harris, Tamara B A1 - Highland, Heather M A1 - Lange, Leslie A A1 - Liu, Yongmei A1 - Mägi, Reedik A1 - Nalls, Mike A A1 - Mathias, Rasika A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - Starr, John M A1 - Tardif, Jean-Claude A1 - Tzoulaki, Ioanna A1 - Velez Edwards, Digna R A1 - Wallentin, Lars A1 - Bartz, Traci M A1 - Becker, Lewis C A1 - Denny, Joshua C A1 - Raffield, Laura M A1 - Rioux, John D A1 - Friedrich, Nele A1 - Fornage, Myriam A1 - Gao, He A1 - Hirschhorn, Joel N A1 - Liewald, David C M A1 - Rich, Stephen S A1 - Uitterlinden, Andre A1 - Bastarache, Lisa A1 - Becker, Diane M A1 - Boerwinkle, Eric A1 - de Denus, Simon A1 - Bottinger, Erwin P A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Lu, Yingchang A1 - Metspalu, Andres A1 - O'Donnell, Chris J A1 - Quarells, Rakale C A1 - Richard, Melissa A1 - Torstenson, Eric S A1 - Taylor, Kent D A1 - Vergnaud, Anne-Claire A1 - Zonderman, Alan B A1 - Crosslin, David R A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kähönen, Mika A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Slater, Andrew J A1 - Dehghan, Abbas A1 - White, Harvey D A1 - Ganesh, Santhi K A1 - Loos, Ruth J F A1 - Esko, Tõnu A1 - Faraday, Nauder A1 - Wilson, James G A1 - Cushman, Mary A1 - Johnson, Andrew D A1 - Edwards, Todd L A1 - Zakai, Neil A A1 - Lettre, Guillaume A1 - Reiner, Alex P A1 - Auer, Paul L AB -

White 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.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract ER - TY - JOUR T1 - Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. JF - Pharmacogenomics J Y1 - 2016 A1 - Floyd, J S A1 - Sitlani, C M A1 - Avery, C L A1 - Noordam, R A1 - Li, X A1 - Smith, A V A1 - Gogarten, S M A1 - Li, J A1 - Broer, L A1 - Evans, D S A1 - Trompet, S A1 - Brody, J A A1 - Stewart, J D A1 - Eicher, J D A1 - Seyerle, A A A1 - Roach, J A1 - Lange, L A A1 - Lin, H J A1 - Kors, J A A1 - Harris, T B A1 - Li-Gao, R A1 - Sattar, N A1 - Cummings, S R A1 - Wiggins, K L A1 - Napier, M D A1 - Stürmer, T A1 - Bis, J C A1 - Kerr, K F A1 - Uitterlinden, A G A1 - Taylor, K D A1 - Stott, D J A1 - de Mutsert, R A1 - Launer, L J A1 - Busch, E L A1 - Méndez-Giráldez, R A1 - Sotoodehnia, N A1 - Soliman, E Z A1 - Li, Y A1 - Duan, Q A1 - Rosendaal, F R A1 - Slagboom, P E A1 - Wilhelmsen, K C A1 - Reiner, A P A1 - Chen, Y-DI A1 - Heckbert, S R A1 - Kaplan, R C A1 - Rice, K M A1 - Jukema, J W A1 - Johnson, A D A1 - Liu, Y A1 - Mook-Kanamori, D O A1 - Gudnason, V A1 - Wilson, J G A1 - Rotter, J I A1 - Laurie, C C A1 - Psaty, B M A1 - Whitsel, E A A1 - Cupples, L A A1 - Stricker, B H AB -

Sulfonylureas, 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.

ER - TY - JOUR T1 - Longitudinal Relationship Between Loneliness and Social Isolation in Older Adults: Results From the Cardiovascular Health Study. JF - J Aging Health Y1 - 2016 A1 - Petersen, Johanna A1 - Kaye, Jeffrey A1 - Jacobs, Peter G A1 - Quinones, Ana A1 - Dodge, Hiroko A1 - Arnold, Alice A1 - Thielke, Stephen AB -

OBJECTIVE: 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.

VL - 28 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26491043?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. JF - Nat Genet Y1 - 2016 A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Bis, Joshua C A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Lu, Yingchang A1 - Weiss, Stefan A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Martin, Lisa W A1 - Chen, Yii-Der Ida A1 - Surendran, Praveen A1 - Drenos, Fotios A1 - Cook, James P A1 - Auer, Paul L A1 - Chu, Audrey Y A1 - Giri, Ayush A1 - Zhao, Wei A1 - Jakobsdottir, Johanna A1 - Lin, Li-An A1 - Stafford, Jeanette M A1 - Amin, Najaf A1 - Mei, Hao A1 - Yao, Jie A1 - Voorman, Arend A1 - Larson, Martin G A1 - Grove, Megan L A1 - Smith, Albert V A1 - Hwang, Shih-Jen A1 - Chen, Han A1 - Huan, Tianxiao A1 - Kosova, Gulum A1 - Stitziel, Nathan O A1 - Kathiresan, Sekar A1 - Samani, Nilesh A1 - Schunkert, Heribert A1 - Deloukas, Panos A1 - Li, Man A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Gorski, Mathias A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Rossouw, Jacques E A1 - Faul, Jessica D A1 - Kardia, Sharon L R A1 - Bouchard, Claude A1 - Raffel, Leslie J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Vasan, Ramachandran S A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Liu, Kiang A1 - Bottinger, Erwin P A1 - Gottesman, Omri A1 - Daw, E Warwick A1 - Giulianini, Franco A1 - Ganesh, Santhi A1 - Salfati, Elias A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Rettig, Rainer A1 - Völzke, Henry A1 - Kim, Eric A1 - Lee, Wen-Jane A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Tsosie, Krystal S A1 - Edwards, Digna R Velez A1 - Liu, Yongmei A1 - Correa, Adolfo A1 - Weir, David R A1 - Völker, Uwe A1 - Ridker, Paul M A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Reiner, Alexander P A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Edwards, Todd L A1 - Chakravarti, Aravinda A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Ehret, Georg B A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Chasman, Daniel I AB -

Meta-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.

VL - 48 IS - 10 ER - TY - JOUR T1 - A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. JF - Hum Mol Genet Y1 - 2016 A1 - de Vries, Paul S A1 - Chasman, Daniel I A1 - Sabater-Lleal, Maria A1 - Chen, Ming-Huei A1 - Huffman, Jennifer E A1 - Steri, Maristella A1 - Tang, Weihong A1 - Teumer, Alexander A1 - Marioni, Riccardo E A1 - Grossmann, Vera A1 - Hottenga, Jouke J A1 - Trompet, Stella A1 - Müller-Nurasyid, Martina A1 - Zhao, Jing Hua A1 - Brody, Jennifer A A1 - Kleber, Marcus E A1 - Guo, Xiuqing A1 - Wang, Jie Jin A1 - Auer, Paul L A1 - Attia, John R A1 - Yanek, Lisa R A1 - Ahluwalia, Tarunveer S A1 - Lahti, Jari A1 - Venturini, Cristina A1 - Tanaka, Toshiko A1 - Bielak, Lawrence F A1 - Joshi, Peter K A1 - Rocanin-Arjo, Ares A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Rose, Lynda M A1 - Oldmeadow, Christopher A1 - Riess, Helene A1 - Mazur, Johanna A1 - Basu, Saonli A1 - Goel, Anuj A1 - Yang, Qiong A1 - Ghanbari, Mohsen A1 - Willemsen, Gonneke A1 - Rumley, Ann A1 - Fiorillo, Edoardo A1 - de Craen, Anton J M A1 - Grotevendt, Anne A1 - Scott, Robert A1 - Taylor, Kent D A1 - Delgado, Graciela E A1 - Yao, Jie A1 - Kifley, Annette A1 - Kooperberg, Charles A1 - Qayyum, Rehan A1 - Lopez, Lorna M A1 - Berentzen, Tina L A1 - Räikkönen, Katri A1 - Mangino, Massimo A1 - Bandinelli, Stefania A1 - Peyser, Patricia A A1 - Wild, Sarah A1 - Trégouët, David-Alexandre A1 - Wright, Alan F A1 - Marten, Jonathan A1 - Zemunik, Tatijana A1 - Morrison, Alanna C A1 - Sennblad, Bengt A1 - Tofler, Geoffrey A1 - de Maat, Moniek P M A1 - de Geus, Eco J C A1 - Lowe, Gordon D A1 - Zoledziewska, Magdalena A1 - Sattar, Naveed A1 - Binder, Harald A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Khaw, Kay-Tee A1 - McKnight, Barbara A1 - Huang, Jie A1 - Jenny, Nancy S A1 - Holliday, Elizabeth G A1 - Qi, Lihong A1 - Mcevoy, Mark G A1 - Becker, Diane M A1 - Starr, John M A1 - Sarin, Antti-Pekka A1 - Hysi, Pirro G A1 - Hernandez, Dena G A1 - Jhun, Min A A1 - Campbell, Harry A1 - Hamsten, Anders A1 - Rivadeneira, Fernando A1 - McArdle, Wendy L A1 - Slagboom, P Eline A1 - Zeller, Tanja A1 - Koenig, Wolfgang A1 - Psaty, Bruce M A1 - Haritunians, Talin A1 - Liu, Jingmin A1 - Palotie, Aarno A1 - Uitterlinden, André G A1 - Stott, David J A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Morange, Pierre-Emmanuel A1 - Wilson, James F A1 - Kardia, Sharon L R A1 - Ferrucci, Luigi A1 - Spector, Tim D A1 - Eriksson, Johan G A1 - Hansen, Torben A1 - Deary, Ian J A1 - Becker, Lewis C A1 - Scott, Rodney J A1 - Mitchell, Paul A1 - März, Winfried A1 - Wareham, Nick J A1 - Peters, Annette A1 - Greinacher, Andreas A1 - Wild, Philipp S A1 - Jukema, J Wouter A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Cucca, Francesco A1 - Tracy, Russell A1 - Watkins, Hugh A1 - Reiner, Alex P A1 - Folsom, Aaron R A1 - Ridker, Paul M A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Strachan, David P A1 - Dehghan, Abbas AB -

Genome-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.

VL - 25 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. JF - J Med Genet Y1 - 2016 A1 - van Leeuwen, Elisabeth M A1 - Sabo, Aniko A1 - Bis, Joshua C A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Smith, Albert V A1 - Feitosa, Mary F A1 - Demissie, Serkalem A1 - Joshi, Peter K A1 - Duan, Qing A1 - Marten, Jonathan A1 - van Klinken, Jan B A1 - Surakka, Ida A1 - Nolte, Ilja M A1 - Zhang, Weihua A1 - Mbarek, Hamdi A1 - Li-Gao, Ruifang A1 - Trompet, Stella A1 - Verweij, Niek A1 - Evangelou, Evangelos A1 - Lyytikäinen, Leo-Pekka A1 - Tayo, Bamidele O A1 - Deelen, Joris A1 - van der Most, Peter J A1 - van der Laan, Sander W A1 - Arking, Dan E A1 - Morrison, Alanna A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Sijbrands, Eric J A1 - Uitterlinden, André G A1 - Mychaleckyj, Josyf C A1 - Campbell, Archie A1 - Hocking, Lynne J A1 - Padmanabhan, Sandosh A1 - Brody, Jennifer A A1 - Rice, Kenneth M A1 - White, Charles C A1 - Harris, Tamara A1 - Isaacs, Aaron A1 - Campbell, Harry A1 - Lange, Leslie A A1 - Rudan, Igor A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Zemunik, Tatijana A1 - Salomaa, Veikko A1 - Kooner, Angad S A1 - Kooner, Jaspal S A1 - Lehne, Benjamin A1 - Scott, William R A1 - Tan, Sian-Tsung A1 - de Geus, Eco J A1 - Milaneschi, Yuri A1 - Penninx, Brenda W J H A1 - Willemsen, Gonneke A1 - de Mutsert, Renée A1 - Ford, Ian A1 - Gansevoort, Ron T A1 - Segura-Lepe, Marcelo P A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Nikus, Kjell A1 - Forrester, Terrence A1 - McKenzie, Colin A A1 - de Craen, Anton J M A1 - de Ruijter, Hester M A1 - Pasterkamp, Gerard A1 - Snieder, Harold A1 - Oldehinkel, Albertine J A1 - Slagboom, P Eline A1 - Cooper, Richard S A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Elliott, Paul A1 - van der Harst, Pim A1 - Jukema, J Wouter A1 - Mook-Kanamori, Dennis O A1 - Boomsma, Dorret I A1 - Chambers, John C A1 - Swertz, Morris A1 - Ripatti, Samuli A1 - Willems van Dijk, Ko A1 - Vitart, Veronique A1 - Polasek, Ozren A1 - Hayward, Caroline A1 - Wilson, James G A1 - Wilson, James F A1 - Gudnason, Vilmundur A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Cupples, L Adrienne A1 - van Duijn, Cornelia M AB -

BACKGROUND: 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.

VL - 53 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27036123?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. JF - J Med Genet Y1 - 2016 A1 - Postmus, Iris A1 - Warren, Helen R A1 - Trompet, Stella A1 - Arsenault, Benoit J A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - de Keyser, Catherine E A1 - Deshmukh, Harshal A A1 - Evans, Daniel S A1 - Feng, QiPing A1 - Li, Xiaohui A1 - Smit, Roelof A J A1 - Smith, Albert V A1 - Sun, Fangui A1 - Taylor, Kent D A1 - Arnold, Alice M A1 - Barnes, Michael R A1 - Barratt, Bryan J A1 - Betteridge, John A1 - Boekholdt, S Matthijs A1 - Boerwinkle, Eric A1 - Buckley, Brendan M A1 - Chen, Y-D Ida A1 - de Craen, Anton J M A1 - Cummings, Steven R A1 - Denny, Joshua C A1 - Dubé, Marie Pierre A1 - Durrington, Paul N A1 - Eiriksdottir, Gudny A1 - Ford, Ian A1 - Guo, Xiuqing A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Kastelein, John J P A1 - Launer, Leonore J A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Lumley, Thomas A1 - McKeigue, Paul M A1 - Munroe, Patricia B A1 - Neil, Andrew A1 - Nickerson, Deborah A A1 - Nyberg, Fredrik A1 - O'Brien, Eoin A1 - O'Donnell, Christopher J A1 - Post, Wendy A1 - Poulter, Neil A1 - Vasan, Ramachandran S A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Sattar, Naveed A1 - Sever, Peter A1 - Shaw-Hawkins, Sue A1 - Shields, Denis C A1 - Slagboom, P Eline A1 - Smith, Nicholas L A1 - Smith, Joshua D A1 - Sotoodehnia, Nona A1 - Stanton, Alice A1 - Stott, David J A1 - Stricker, Bruno H A1 - Stürmer, Til A1 - Uitterlinden, André G A1 - Wei, Wei-Qi A1 - Westendorp, Rudi G J A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Wilke, Russell A A1 - Ballantyne, Christie M A1 - Colhoun, Helen M A1 - Cupples, L Adrienne A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Hitman, Graham A1 - Palmer, Colin N A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Stafford, Jeanette M A1 - Stein, Charles M A1 - Tardif, Jean-Claude A1 - Caulfield, Mark J A1 - Jukema, J Wouter A1 - Rotter, Jerome I A1 - Krauss, Ronald M AB -

BACKGROUND: 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.

VL - 53 IS - 12 ER - TY - JOUR T1 - Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Natarajan, Pradeep A1 - Bis, Joshua C A1 - Bielak, Lawrence F A1 - Cox, Amanda J A1 - Dörr, Marcus A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Isaacs, Aaron A1 - Jhun, Min A A1 - Kavousi, Maryam A1 - Li-Gao, Ruifang A1 - Lyytikäinen, Leo-Pekka A1 - Marioni, Riccardo E A1 - Schminke, Ulf A1 - Stitziel, Nathan O A1 - Tada, Hayato A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Baber, Usman A1 - Borecki, Ingrid B A1 - Carr, J Jeffrey A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - de Jong, Pim A A1 - de Koning, Harry A1 - de Vos, Bob D A1 - Demirkan, Ayse A1 - Fuster, Valentin A1 - Franco, Oscar H A1 - Goodarzi, Mark O A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hoffmann, Udo A1 - Hofman, Albert A1 - Išgum, Ivana A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Massaro, Joseph A1 - Mehran, Roxana A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - de Mutsert, Renée A1 - Newman, Anne B A1 - Nguyen, Khanh-Dung A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Oudkerk, Matthijs A1 - Pankow, James S A1 - Peloso, Gina M A1 - Post, Wendy A1 - Province, Michael A A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rivadeneira, Fernando A1 - Rosendaal, Frits A1 - Sartori, Samantha A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Lugt, Aad A1 - Völker, Uwe A1 - Wardlaw, Joanna M A1 - Wassel, Christina L A1 - Weiss, Stefan A1 - Wojczynski, Mary K A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dehghan, Abbas A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Lehtimäki, Terho A1 - Mathias, Rasika A1 - Mook-Kanamori, Dennis O A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Kathiresan, Sekar A1 - Peyser, Patricia A A1 - O'Donnell, Christopher J AB -

BACKGROUND: -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.

ER - TY - JOUR T1 - Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis. JF - Lancet Diabetes Endocrinol Y1 - 2016 A1 - Willeit, Peter A1 - Kaptoge, Stephen A1 - Welsh, Paul A1 - Butterworth, Adam A1 - Chowdhury, Rajiv A1 - Spackman, Sarah A1 - Pennells, Lisa A1 - Gao, Pei A1 - Burgess, Stephen A1 - Freitag, Daniel A1 - Sweeting, Michael A1 - Wood, Angela A1 - Cook, Nancy A1 - Judd, Suzanne A1 - Trompet, Stella A1 - Nambi, Vijay A1 - Olsen, Michael A1 - Everett, Brendan A1 - Kee, Frank A1 - Arnlöv, Johan A1 - Salomaa, Veikko A1 - Levy, Daniel A1 - Kauhanen, Jussi A1 - Laukkanen, Jari A1 - Kavousi, Maryam A1 - Ninomiya, Toshiharu A1 - Casas, Juan-Pablo A1 - Daniels, Lori A1 - Lind, Lars A1 - Kistorp, Caroline A1 - Rosenberg, Jens A1 - Mueller, Thomas A1 - Rubattu, Speranza A1 - Panagiotakos, Demosthenes A1 - Franco, Oscar A1 - de Lemos, James A1 - Luchner, Andreas A1 - Kizer, Jorge A1 - Kiechl, Stefan A1 - Salonen, Jukka A1 - Goya Wannamethee, S A1 - de Boer, Rudolf A1 - Nordestgaard, Børge A1 - Andersson, Jonas A1 - Jørgensen, Torben A1 - Melander, Olle A1 - Ballantyne, Christie A1 - DeFilippi, Christopher A1 - Ridker, Paul A1 - Cushman, Mary A1 - Rosamond, Wayne A1 - Thompson, Simon A1 - Gudnason, Vilmundur A1 - Sattar, Naveed A1 - Danesh, John A1 - Di Angelantonio, Emanuele KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Female KW - Humans KW - Male KW - Middle Aged KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Prospective Studies KW - Risk Assessment AB -

BACKGROUND: 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.

VL - 4 IS - 10 ER - TY - JOUR T1 - A novel Alzheimer disease locus located near the gene encoding tau protein. JF - Mol Psychiatry Y1 - 2016 A1 - Jun, G A1 - Ibrahim-Verbaas, C A A1 - Vronskaya, M A1 - Lambert, J-C A1 - Chung, J A1 - Naj, A C A1 - Kunkle, B W A1 - Wang, L-S A1 - Bis, J C A1 - Bellenguez, C A1 - Harold, D A1 - Lunetta, K L A1 - DeStefano, A L A1 - Grenier-Boley, B A1 - Sims, R A1 - Beecham, G W A1 - Smith, A V A1 - Chouraki, V A1 - Hamilton-Nelson, K L A1 - Ikram, M A A1 - Fiévet, N A1 - Denning, N A1 - Martin, E R A1 - Schmidt, H A1 - Kamatani, Y A1 - Dunstan, M L A1 - Valladares, O A1 - Laza, A R A1 - Zelenika, D A1 - Ramirez, A A1 - Foroud, T M A1 - Choi, S-H A1 - Boland, A A1 - Becker, T A1 - Kukull, W A A1 - van der Lee, S J A1 - Pasquier, F A1 - Cruchaga, C A1 - Beekly, D A1 - Fitzpatrick, A L A1 - Hanon, O A1 - Gill, M A1 - Barber, R A1 - Gudnason, V A1 - Campion, D A1 - Love, S A1 - Bennett, D A A1 - Amin, N A1 - Berr, C A1 - Tsolaki, Magda A1 - Buxbaum, J D A1 - Lopez, O L A1 - Deramecourt, V A1 - Fox, N C A1 - Cantwell, L B A1 - Tárraga, L A1 - Dufouil, C A1 - Hardy, J A1 - Crane, P K A1 - Eiriksdottir, G A1 - Hannequin, D A1 - Clarke, R A1 - Evans, D A1 - Mosley, T H A1 - Letenneur, L A1 - Brayne, C A1 - Maier, W A1 - De Jager, P A1 - Emilsson, V A1 - Dartigues, J-F A1 - Hampel, H A1 - Kamboh, M I A1 - de Bruijn, R F A G A1 - Tzourio, C A1 - Pastor, P A1 - Larson, E B A1 - Rotter, J I A1 - O'Donovan, M C A1 - Montine, T J A1 - Nalls, M A A1 - Mead, S A1 - Reiman, E M A1 - Jonsson, P V A1 - Holmes, C A1 - St George-Hyslop, P H A1 - Boada, M A1 - Passmore, P A1 - Wendland, J R A1 - Schmidt, R A1 - Morgan, K A1 - Winslow, A R A1 - Powell, J F A1 - Carasquillo, M A1 - Younkin, S G A1 - Jakobsdóttir, J A1 - Kauwe, J S K A1 - Wilhelmsen, K C A1 - Rujescu, D A1 - Nöthen, M M A1 - Hofman, A A1 - Jones, L A1 - Haines, J L A1 - Psaty, B M A1 - Van Broeckhoven, C A1 - Holmans, P A1 - Launer, L J A1 - Mayeux, R A1 - Lathrop, M A1 - Goate, A M A1 - Escott-Price, V A1 - Seshadri, S A1 - Pericak-Vance, M A A1 - Amouyel, P A1 - Williams, J A1 - van Duijn, C M A1 - Schellenberg, G D A1 - Farrer, L A KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Chromosomes, Human, Pair 17 KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - tau Proteins AB -

APOE 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.

VL - 21 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25778476?dopt=Abstract ER - TY - JOUR T1 - Novel Genetic Loci Associated With Retinal Microvascular Diameter. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Li, Xiaohui A1 - Jakobsdottir, Johanna A1 - Cheng, Ching-Yu A1 - Brody, Jennifer A A1 - Cotch, Mary Frances A1 - McKnight, Barbara A1 - Klein, Ronald A1 - Wang, Jie Jin A1 - Kifley, Annette A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Klein, Barbara E K A1 - Raffel, Leslie J A1 - Li, Xiang A1 - Ikram, M Arfan A1 - Klaver, Caroline C A1 - van der Lee, Sven J A1 - Mutlu, Unal A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Mitchell, Paul A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Wong, Tien Y AB -

BACKGROUND: 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.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26567291?dopt=Abstract ER - TY - JOUR T1 - {Novel genetic loci underlying human intracranial volume identified through genome-wide association JF - Nat Neurosci Y1 - 2016 A1 - Adams, H. H. A1 - Hibar, D. P. A1 - Chouraki, V. A1 - Stein, J. L. A1 - Nyquist, P. A. A1 - Renter?a, M. E. A1 - Trompet, S. A1 - Arias-Vasquez, A. A1 - Seshadri, S. A1 - Desrivi?res, S. A1 - Beecham, A. H. A1 - Jahanshad, N. A1 - Wittfeld, K. A1 - van der Lee, S. J. A1 - Abramovic, L. A1 - Alhusaini, S. A1 - Amin, N. A1 - Andersson, M. A1 - Arfanakis, K. A1 - Aribisala, B. S. A1 - Armstrong, N. J. A1 - Athanasiu, L. A1 - Axelsson, T. A1 - Beiser, A. A1 - Bernard, M. A1 - Bis, J. C. A1 - Blanken, L. M. A1 - Blanton, S. H. A1 - Bohlken, M. M. A1 - Boks, M. P. A1 - Bralten, J. A1 - Brickman, A. M. A1 - Carmichael, O. A1 - Chakravarty, M. M. A1 - Chauhan, G. A1 - Chen, Q. A1 - Ching, C. R. A1 - Cuellar-Partida, G. A1 - Braber, A. D. A1 - Doan, N. T. A1 - Ehrlich, S. A1 - Filippi, I. A1 - Ge, T. A1 - Giddaluru, S. A1 - Goldman, A. L. A1 - Gottesman, R. F. A1 - Greven, C. U. A1 - Grimm, O. A1 - Griswold, M. E. A1 - Guadalupe, T. A1 - Hass, J. A1 - Haukvik, U. K. A1 - Hilal, S. A1 - Hofer, E. A1 - Hoehn, D. A1 - Holmes, A. J. A1 - Hoogman, M. A1 - Janowitz, D. A1 - Jia, T. A1 - Kasperaviciute, D. A1 - Kim, S. A1 - Klein, M. A1 - Kraemer, B. A1 - Lee, P. H. A1 - Liao, J. A1 - Liewald, D. C. A1 - Lopez, L. M. A1 - Luciano, M. A1 - Macare, C. A1 - Marquand, A. A1 - Matarin, M. A1 - Mather, K. A. A1 - Mattheisen, M. A1 - Mazoyer, B. A1 - McKay, D. R. A1 - McWhirter, R. A1 - Milaneschi, Y. A1 - Mirza-Schreiber, N. A1 - Muetzel, R. L. A1 - Maniega, S. M. A1 - Nho, K. A1 - Nugent, A. C. A1 - Loohuis, L. M. A1 - Oosterlaan, J. A1 - Papmeyer, M. A1 - Pappa, I. A1 - Pirpamer, L. A1 - Pudas, S. A1 - P?tz, B. A1 - Rajan, K. B. A1 - Ramasamy, A. A1 - Richards, J. S. A1 - Risacher, S. L. A1 - Roiz-Santia?ez, R. A1 - Rommelse, N. A1 - Rose, E. J. A1 - Royle, N. A. A1 - Rundek, T. A1 - S?mann, P. G. A1 - Satizabal, C. L. A1 - Schmaal, L. A1 - Schork, A. J. A1 - Shen, L. A1 - Shin, J. A1 - Shumskaya, E. A1 - Smith, A. V. A1 - Sprooten, E. A1 - Strike, L. T. A1 - Teumer, A. A1 - Thomson, R. A1 - Tordesillas-Gutierrez, D. A1 - Toro, R. A1 - Trabzuni, D. A1 - Vaidya, D. A1 - van der Grond, J. A1 - van der Meer, D. A1 - Van Donkelaar, M. M. A1 - Van Eijk, K. R. A1 - Van Erp, T. G. A1 - van Rooij, D. A1 - Walton, E. A1 - Westlye, L. T. A1 - Whelan, C. D. A1 - Windham, B. G. A1 - Winkler, A. M. A1 - Woldehawariat, G. A1 - Wolf, C. A1 - Wolfers, T. A1 - Xu, B. A1 - Yanek, L. R. A1 - Yang, J. A1 - Zijdenbos, A. A1 - Zwiers, M. P. A1 - Agartz, I. A1 - Aggarwal, N. T. A1 - Almasy, L. A1 - Ames, D. A1 - Amouyel, P. A1 - Andreassen, O. A. A1 - Arepalli, S. A1 - Assareh, A. A. A1 - Barral, S. A1 - Bastin, M. E. A1 - Becker, D. M. A1 - Becker, J. T. A1 - Bennett, D. A. A1 - Blangero, J. A1 - van Bokhoven, H. A1 - Boomsma, D. I. A1 - Brodaty, H. A1 - Brouwer, R. M. A1 - Brunner, H. G. A1 - Buckner, R. L. A1 - Buitelaar, J. K. A1 - Bulayeva, K. B. A1 - Cahn, W. A1 - Calhoun, V. D. A1 - Cannon, D. M. A1 - Cavalleri, G. L. A1 - Chen, C. A1 - Cheng, C. Y. A1 - Cichon, S. A1 - Cookson, M. R. A1 - Corvin, A. A1 - Crespo-Facorro, B. A1 - Curran, J. E. A1 - Czisch, M. A1 - Dale, A. M. A1 - Davies, G. E. A1 - De Geus, E. J. A1 - De Jager, P. L. A1 - de Zubicaray, G. I. A1 - Delanty, N. A1 - Depondt, C. A1 - DeStefano, A. L. A1 - Dillman, A. A1 - Djurovic, S. A1 - Donohoe, G. A1 - Drevets, W. C. A1 - Duggirala, R. A1 - Dyer, T. D. A1 - Erk, S. A1 - Espeseth, T. A1 - Evans, D. A. A1 - Fedko, I. O. A1 - Fern?ndez, G. A1 - Ferrucci, L. A1 - Fisher, S. E. A1 - Fleischman, D. A. A1 - Ford, I. A1 - Foroud, T. M. A1 - Fox, P. T. A1 - Francks, C. A1 - Fukunaga, M. A1 - Gibbs, J. R. A1 - Glahn, D. C. A1 - Gollub, R. L. A1 - G?ring, H. H. A1 - Grabe, H. J. A1 - Green, R. C. A1 - Gruber, O. A1 - Gudnason, V. A1 - Guelfi, S. A1 - Hansell, N. K. A1 - Hardy, J. A1 - Hartman, C. A. A1 - Hashimoto, R. A1 - Hegenscheid, K. A1 - Heinz, A. A1 - Le Hellard, S. A1 - Hernandez, D. G. A1 - Heslenfeld, D. J. A1 - Ho, B. C. A1 - Hoekstra, P. J. A1 - Hoffmann, W. A1 - Hofman, A. A1 - Holsboer, F. A1 - Homuth, G. A1 - Hosten, N. A1 - Hottenga, J. J. A1 - Hulshoff Pol, H. E. A1 - Ikeda, M. A1 - Ikram, M. K. A1 - Jack, C. R. A1 - Jenkinson, M. A1 - Johnson, R. A1 - J?nsson, E. G. A1 - Jukema, J. W. A1 - Kahn, R. S. A1 - Kanai, R. A1 - Kloszewska, I. A1 - Knopman, D. S. A1 - Kochunov, P. A1 - Kwok, J. B. A1 - Lawrie, S. M. A1 - Lema?tre, H. A1 - Liu, X. A1 - Longo, D. L. A1 - Longstreth, W. T. A1 - Lopez, O. L. A1 - Lovestone, S. A1 - Martinez, O. A1 - Martinot, J. L. A1 - Mattay, V. S. A1 - McDonald, C. A1 - McIntosh, A. M. A1 - McMahon, K. L. A1 - McMahon, F. J. A1 - Mecocci, P. A1 - Melle, I. A1 - Meyer-Lindenberg, A. A1 - Mohnke, S. A1 - Montgomery, G. W. A1 - Morris, D. W. A1 - Mosley, T. H. A1 - M?hleisen, T. W. A1 - M?ller-Myhsok, B. A1 - Nalls, M. A. A1 - Nauck, M. A1 - Nichols, T. E. A1 - Niessen, W. J. A1 - N?then, M. M. A1 - Nyberg, L. A1 - Ohi, K. A1 - Olvera, R. L. A1 - Ophoff, R. A. A1 - Pandolfo, M. A1 - Paus, T. A1 - Pausova, Z. A1 - Penninx, B. W. A1 - Pike, G. B. A1 - Potkin, S. G. A1 - Psaty, B. M. A1 - Reppermund, S. A1 - Rietschel, M. A1 - Roffman, J. L. A1 - Romanczuk-Seiferth, N. A1 - Rotter, J. I. A1 - Ryten, M. A1 - Sacco, R. L. A1 - Sachdev, P. S. A1 - Saykin, A. J. A1 - Schmidt, R. A1 - Schofield, P. R. A1 - Sigurdsson, S. A1 - Simmons, A. A1 - Singleton, A. A1 - Sisodiya, S. M. A1 - Smith, C. A1 - Smoller, J. W. A1 - Soininen, H. A1 - Srikanth, V. A1 - Steen, V. M. A1 - Stott, D. J. A1 - Sussmann, J. E. A1 - Thalamuthu, A. A1 - Tiemeier, H. A1 - Toga, A. W. A1 - Traynor, B. J. A1 - Troncoso, J. A1 - Turner, J. A. A1 - Tzourio, C. A1 - Uitterlinden, A. G. A1 - Hern?ndez, M. C. A1 - Van der Brug, M. A1 - van der Lugt, A. A1 - Van der Wee, N. J. A1 - van Duijn, C. M. A1 - Van Haren, N. E. A1 - Van T Ent, D. A1 - van Tol, M. J. A1 - Vardarajan, B. N. A1 - Veltman, D. J. A1 - Vernooij, M. W. A1 - V?lzke, H. A1 - Walter, H. A1 - Wardlaw, J. M. A1 - Wassink, T. H. A1 - Weale, M. E. A1 - Weinberger, D. R. A1 - Weiner, M. W. A1 - Wen, W. A1 - Westman, E. A1 - White, T. A1 - Wong, T. Y. A1 - Wright, C. B. A1 - Zielke, H. R. A1 - Zonderman, A. B. A1 - Deary, I. J. A1 - DeCarli, C. A1 - Schmidt, H. A1 - Martin, N. G. A1 - De Craen, A. J. A1 - Wright, M. J. A1 - Launer, L. J. A1 - Schumann, G. A1 - Fornage, M. A1 - Franke, B. A1 - Debette, S. A1 - Medland, S. E. A1 - Ikram, M. A. A1 - Thompson, P. M. AB - Intracranial 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 (ρgenetic = 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. VL - 19 ER - TY - JOUR T1 - Physical Activity and Risk of Coronary Heart Disease and Stroke in Older Adults: The Cardiovascular Health Study. JF - Circulation Y1 - 2016 A1 - Soares-Miranda, Luisa A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Mozaffarian, Dariush KW - Aged KW - Aged, 80 and over KW - Coronary Disease KW - Female KW - Follow-Up Studies KW - Health Status KW - Humans KW - Leisure Activities KW - Male KW - Motor Activity KW - Proportional Hazards Models KW - Prospective Studies KW - Sampling Studies KW - Stroke KW - United States KW - Walking AB -

BACKGROUND: 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.

VL - 133 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26538582?dopt=Abstract ER - TY - JOUR T1 - Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. JF - Am J Hum Genet Y1 - 2016 A1 - Eicher, John D A1 - Chami, Nathalie A1 - Kacprowski, Tim A1 - Nomura, Akihiro A1 - Chen, Ming-Huei A1 - Yanek, Lisa R A1 - Tajuddin, Salman M A1 - Schick, Ursula M A1 - Slater, Andrew J A1 - Pankratz, Nathan A1 - Polfus, Linda A1 - Schurmann, Claudia A1 - Giri, Ayush A1 - Brody, Jennifer A A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Hill, W David A1 - Pazoki, Raha A1 - Elliot, Paul A1 - Evangelou, Evangelos A1 - Tzoulaki, Ioanna A1 - Gao, He A1 - Vergnaud, Anne-Claire A1 - Mathias, Rasika A A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Burt, Amber A1 - Crosslin, David R A1 - Lyytikäinen, Leo-Pekka A1 - Nikus, Kjell A1 - Hernesniemi, Jussi A1 - Kähönen, Mika A1 - Raitoharju, Emma A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Lehtimäki, Terho A1 - Cushman, Mary A1 - Zakai, Neil A A1 - Nickerson, Deborah A A1 - Raffield, Laura M A1 - Quarells, Rakale A1 - Willer, Cristen J A1 - Peloso, Gina M A1 - Abecasis, Goncalo R A1 - Liu, Dajiang J A1 - Deloukas, Panos A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Fornage, Myriam A1 - Richard, Melissa A1 - Tardif, Jean-Claude A1 - Rioux, John D A1 - Dubé, Marie-Pierre A1 - de Denus, Simon A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Smith, Albert Vernon A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Gudnason, Vilmundur A1 - Velez Edwards, Digna R A1 - Torstenson, Eric S A1 - Liu, Yongmei A1 - Tracy, Russell P A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Highland, Heather M A1 - Boerwinkle, Eric A1 - Li, Jin A1 - Lange, Ethan A1 - Wilson, James G A1 - Mihailov, Evelin A1 - Mägi, Reedik A1 - Hirschhorn, Joel A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Vacchi-Suzzi, Caterina A1 - Nalls, Mike A A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Engström, Gunnar A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - O'Donoghue, Michelle L A1 - Waterworth, Dawn M A1 - Wallentin, Lars A1 - White, Harvey D A1 - Floyd, James S A1 - Bartz, Traci M A1 - Rice, Kenneth M A1 - Psaty, Bruce M A1 - Starr, J M A1 - Liewald, David C M A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Greinacher, Andreas A1 - Völker, Uwe A1 - Thiele, Thomas A1 - Völzke, Henry A1 - van Rooij, Frank J A A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Dehghan, Abbas A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Kathiresan, Sekar A1 - Faraday, Nauder A1 - Auer, Paul L A1 - Reiner, Alex P A1 - Lettre, Guillaume A1 - Johnson, Andrew D AB -

Platelet 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.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract ER - TY - JOUR T1 - Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes. JF - Circ Heart Fail Y1 - 2016 A1 - Ho, Jennifer E A1 - Enserro, Danielle A1 - Brouwers, Frank P A1 - Kizer, Jorge R A1 - Shah, Sanjiv J A1 - Psaty, Bruce M A1 - Bartz, Traci M A1 - Santhanakrishnan, Rajalakshmi A1 - Lee, Douglas S A1 - Chan, Cheeling A1 - Liu, Kiang A1 - Blaha, Michael J A1 - Hillege, Hans L A1 - van der Harst, Pim A1 - van Gilst, Wiek H A1 - Kop, Willem J A1 - Gansevoort, Ron T A1 - Vasan, Ramachandran S A1 - Gardin, Julius M A1 - Levy, Daniel A1 - Gottdiener, John S A1 - de Boer, Rudolf A A1 - Larson, Martin G AB -

BACKGROUND: 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.

VL - 9 IS - 6 ER - TY - JOUR T1 - A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. JF - Nat Commun Y1 - 2016 A1 - Ried, Janina S A1 - Jeff M, Janina A1 - Chu, Audrey Y A1 - Bragg-Gresham, Jennifer L A1 - van Dongen, Jenny A1 - Huffman, Jennifer E A1 - Ahluwalia, Tarunveer S A1 - Cadby, Gemma A1 - Eklund, Niina A1 - Eriksson, Joel A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Goel, Anuj A1 - Gorski, Mathias A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Jackson, Anne U A1 - Jokinen, Eero A1 - Kanoni, Stavroula A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Mangino, Massimo A1 - Medina-Gómez, Carolina A1 - Monda, Keri L A1 - Nolte, Ilja M A1 - Perusse, Louis A1 - Prokopenko, Inga A1 - Qi, Lu A1 - Rose, Lynda M A1 - Salvi, Erika A1 - Smith, Megan T A1 - Snieder, Harold A1 - Stančáková, Alena A1 - Ju Sung, Yun A1 - Tachmazidou, Ioanna A1 - Teumer, Alexander A1 - Thorleifsson, Gudmar A1 - van der Harst, Pim A1 - Walker, Ryan W A1 - Wang, Sophie R A1 - Wild, Sarah H A1 - Willems, Sara M A1 - Wong, Andrew A1 - Zhang, Weihua A1 - Albrecht, Eva A1 - Couto Alves, Alexessander A1 - Bakker, Stephan J L A1 - Barlassina, Cristina A1 - Bartz, Traci M A1 - Beilby, John A1 - Bellis, Claire A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Blangero, John A1 - Blüher, Matthias A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chen, Yii-Der Ida A1 - Chiang, Charleston W K A1 - Chines, Peter S A1 - Collins, Francis S A1 - Cucca, Fracensco A1 - Cupples, L Adrienne A1 - D'Avila, Francesca A1 - de Geus, Eco J C A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Döring, Angela A1 - Eriksson, Johan G A1 - Farmaki, Aliki-Eleni A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Forouhi, Nita G A1 - Friedrich, Nele A1 - Gjesing, Anette Prior A1 - Glorioso, Nicola A1 - Graff, Mariaelisa A1 - Grallert, Harald A1 - Grarup, Niels A1 - Gräßler, Jürgen A1 - Grewal, Jagvir A1 - Hamsten, Anders A1 - Harder, Marie Neergaard A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hastie, Nicholas A1 - Hattersley, Andrew Tym A1 - Havulinna, Aki S A1 - Heliövaara, Markku A1 - Hillege, Hans A1 - Hofman, Albert A1 - Holmen, Oddgeir A1 - Homuth, Georg A1 - Hottenga, Jouke-Jan A1 - Hui, Jennie A1 - Husemoen, Lise Lotte A1 - Hysi, Pirro G A1 - Isaacs, Aaron A1 - Ittermann, Till A1 - Jalilzadeh, Shapour A1 - James, Alan L A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Marie Justesen, Johanne A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Karaleftheri, Maria A1 - Tee Khaw, Kay A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kinnunen, Leena A1 - Knekt, Paul B A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooner, Ishminder K A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyriakou, Theodosios A1 - Laitinen, Tomi A1 - Langenberg, Claudia A1 - Lewin, Alexandra M A1 - Lichtner, Peter A1 - Lindgren, Cecilia M A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Lorbeer, Roberto A1 - Lorentzon, Mattias A1 - Luben, Robert A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Manunta, Paolo A1 - Leach, Irene Mateo A1 - McArdle, Wendy L A1 - McKnight, Barbara A1 - Mohlke, Karen L A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Mills, Rebecca A1 - Montasser, May E A1 - Morris, Andrew P A1 - Müller, Gabriele A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Osmond, Clive A1 - Palotie, Aarno A1 - Pankow, James S A1 - Paternoster, Lavinia A1 - Penninx, Brenda W A1 - Pichler, Irene A1 - Pilia, Maria G A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rayner, Nigel W A1 - Ribel-Madsen, Rasmus A1 - Rice, Treva K A1 - Richards, Marcus A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Ryan, Kathy A A1 - Sanna, Serena A1 - Sarzynski, Mark A A1 - Scholtens, Salome A1 - Scott, Robert A A1 - Sebert, Sylvain A1 - Southam, Lorraine A1 - Sparsø, Thomas Hempel A1 - Steinthorsdottir, Valgerdur A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Tönjes, Anke A1 - Tsafantakis, Emmanouil A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Vartiainen, Erkki A1 - Venturini, Cristina A1 - Verweij, Niek A1 - Viikari, Jorma S A1 - Vitart, Veronique A1 - Vohl, Marie-Claude A1 - Vonk, Judith M A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Winkler, Thomas W A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Zillikens, M Carola A1 - Boomsma, Dorret I A1 - Bouchard, Claude A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Cusi, Daniele A1 - Gansevoort, Ron T A1 - Gieger, Christian A1 - Hansen, Torben A1 - Hicks, Andrew A A1 - Hu, Frank A1 - Hveem, Kristian A1 - Jarvelin, Marjo-Riitta A1 - Kajantie, Eero A1 - Kooner, Jaspal S A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Metspalu, Andres A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Puolijoki, Hannu A1 - Rauramaa, Rainer A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Shudiner, Alan R A1 - Smit, Jan H A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Tremblay, Angelo A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Zeggini, Eleftheria A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - van Duijn, Cornelia M A1 - Fox, Caroline A1 - Groop, Leif C A1 - Heid, Iris M A1 - Hunter, David J A1 - Kaplan, Robert C A1 - McCarthy, Mark I A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Thorsteinsdottir, Unnur A1 - Strachan, David P A1 - Frayling, Timothy A1 - Hirschhorn, Joel N A1 - Müller-Nurasyid, Martina A1 - Loos, Ruth J F KW - Anthropometry KW - Body Size KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Models, Genetic KW - Principal Component Analysis AB -

Large 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.

VL - 7 ER - TY - JOUR T1 - Prospective study of γ' fibrinogen and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE). JF - Thromb Res Y1 - 2016 A1 - Folsom, Aaron R A1 - Tang, Weihong A1 - George, Kristen M A1 - Heckbert, Susan R A1 - MacLehose, Richard F A1 - Cushman, Mary A1 - Pankow, James S AB -

INTRODUCTION: 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.

VL - 139 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26916295?dopt=Abstract ER - TY - JOUR T1 - Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Yu, Bing A1 - Pulit, Sara L A1 - Hwang, Shih-Jen A1 - Brody, Jennifer A A1 - Amin, Najaf A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Burke, Gregory L A1 - Chakravarti, Aravinda A1 - Correa, Adolfo A1 - Dreisbach, Albert W A1 - Franco, Oscar H A1 - Ehret, Georg B A1 - Franceschini, Nora A1 - Hofman, Albert A1 - Lin, Dan-Yu A1 - Metcalf, Ginger A A1 - Musani, Solomon K A1 - Muzny, Donna A1 - Palmas, Walter A1 - Raffel, Leslie A1 - Reiner, Alex A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Veeraraghavan, Narayanan A1 - Fox, Ervin A1 - Guo, Xiuqing A1 - North, Kari E A1 - Gibbs, Richard A A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Morrison, Alanna C AB -

BACKGROUND: 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.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract ER - TY - JOUR T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. JF - PLoS Genet Y1 - 2016 A1 - Jakobsdottir, Johanna A1 - van der Lee, Sven J A1 - Bis, Joshua C A1 - Chouraki, Vincent A1 - Li-Kroeger, David A1 - Yamamoto, Shinya A1 - Grove, Megan L A1 - Naj, Adam A1 - Vronskaya, Maria A1 - Salazar, Jose L A1 - DeStefano, Anita L A1 - Brody, Jennifer A A1 - Smith, Albert V A1 - Amin, Najaf A1 - Sims, Rebecca A1 - Ibrahim-Verbaas, Carla A A1 - Choi, Seung-Hoan A1 - Satizabal, Claudia L A1 - Lopez, Oscar L A1 - Beiser, Alexa A1 - Ikram, M Arfan A1 - Garcia, Melissa E A1 - Hayward, Caroline A1 - Varga, Tibor V A1 - Ripatti, Samuli A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Rolandsson, Olov A1 - Jansson, Jan-Håkon A1 - Porteous, David J A1 - Salomaa, Veikko A1 - Eiriksdottir, Gudny A1 - Rice, Kenneth M A1 - Bellen, Hugo J A1 - Levy, Daniel A1 - Uitterlinden, André G A1 - Emilsson, Valur A1 - Rotter, Jerome I A1 - Aspelund, Thor A1 - O'Donnell, Christopher J A1 - Fitzpatrick, Annette L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Wang, Li-San A1 - Williams, Julie A1 - Schellenberg, Gerard D A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Shulman, Joshua M A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M AB -

We 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.

VL - 12 IS - 10 ER - TY - JOUR T1 - Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. JF - Mol Psychiatry Y1 - 2016 A1 - Olfson, E A1 - Saccone, N L A1 - Johnson, E O A1 - Chen, L-S A1 - Culverhouse, R A1 - Doheny, K A1 - Foltz, S M A1 - Fox, L A1 - Gogarten, S M A1 - Hartz, S A1 - Hetrick, K A1 - Laurie, C C A1 - Marosy, B A1 - Amin, N A1 - Arnett, D A1 - Barr, R G A1 - Bartz, T M A1 - Bertelsen, S A1 - Borecki, I B A1 - Brown, M R A1 - Chasman, D I A1 - van Duijn, C M A1 - Feitosa, M F A1 - Fox, E R A1 - Franceschini, N A1 - Franco, O H A1 - Grove, M L A1 - Guo, X A1 - Hofman, A A1 - Kardia, S L R A1 - Morrison, A C A1 - Musani, S K A1 - Psaty, B M A1 - Rao, D C A1 - Reiner, A P A1 - Rice, K A1 - Ridker, P M A1 - Rose, L M A1 - Schick, U M A1 - Schwander, K A1 - Uitterlinden, A G A1 - Vojinovic, D A1 - Wang, J-C A1 - Ware, E B A1 - Wilson, G A1 - Yao, J A1 - Zhao, W A1 - Breslau, N A1 - Hatsukami, D A1 - Stitzel, J A A1 - Rice, J A1 - Goate, A A1 - Bierut, L J AB -

The 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.

VL - 21 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26239294?dopt=Abstract ER - TY - JOUR T1 - Relation of coagulation factor XI with incident coronary heart disease and stroke: the Cardiovascular Health Study. JF - Blood Coagul Fibrinolysis Y1 - 2016 A1 - Appiah, Duke A1 - Fashanu, Oluwaseun E A1 - Heckbert, Susa R A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Folsom, Aaron R AB -

The 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.

ER - TY - JOUR T1 - Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2016 A1 - Brutsaert, Erika F A1 - Shitole, Sanyog A1 - Biggs, Mary Lou A1 - Mukamal, Kenneth J A1 - deBoer, Ian H A1 - Thacker, Evan L A1 - Barzilay, Joshua I A1 - Djoussé, Luc A1 - Ix, Joachim H A1 - Smith, Nicholas L A1 - Kaplan, Robert C A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kizer, Jorge R KW - Aged KW - Aging KW - Blood Glucose KW - Cardiovascular Diseases KW - Fasting KW - Female KW - Follow-Up Studies KW - Glucose KW - Glucose Tolerance Test KW - Health Surveys KW - Humans KW - Incidence KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Survival Rate KW - United States AB -

BACKGROUND: 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.

VL - 71 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26314953?dopt=Abstract ER - TY - JOUR T1 - Risk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study. JF - Cerebrovasc Dis Extra Y1 - 2016 A1 - Garg, Parveen K A1 - Koh, Willam J H A1 - Delaney, Joseph A A1 - Halm, Ethan A A1 - Hirsch, Calvin H A1 - Longstreth, William T A1 - Mukamal, Kenneth J A1 - Kucharska-Newton, Anna A1 - Polak, Joseph F A1 - Curtis, Lesley AB -

BACKGROUND: 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.

VL - 6 IS - 3 ER - TY - JOUR T1 - Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment. JF - Pharmacogenomics Y1 - 2016 A1 - Smit, Roelof Aj A1 - Postmus, Iris A1 - Trompet, Stella A1 - Barnes, Michael R A1 - Warren, Helen A1 - Arsenault, Benoit J A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Hitman, Graham A A1 - Krauss, Ronald M A1 - Li, Xiaohui A1 - Psaty, Bruce M A1 - Stein, Charles M A1 - Rotter, Jerome I A1 - Jukema, J Wouter KW - Cholesterol, LDL KW - Genetic Predisposition to Disease KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide KW - Triglycerides AB -

AIMS: 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.

VL - 17 IS - 15 ER - TY - JOUR T1 - Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population. JF - J Am Heart Assoc Y1 - 2016 A1 - Parikh, Ravi H A1 - Seliger, Stephen L A1 - Christenson, Robert A1 - Gottdiener, John S A1 - Psaty, Bruce M A1 - deFilippi, Christopher R AB -

BACKGROUND: 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.

VL - 5 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27481133?dopt=Abstract ER - TY - JOUR T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2016 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y AB -

Genome-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.

ER - TY - JOUR T1 - Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study. JF - Circulation Y1 - 2016 A1 - Psaty, Bruce M A1 - Delaney, Joseph A A1 - Arnold, Alice M A1 - Curtis, Lesley H A1 - Fitzpatrick, Annette L A1 - Heckbert, Susan R A1 - McKnight, Barbara A1 - Ives, Diane A1 - Gottdiener, John S A1 - Kuller, Lewis H A1 - Longstreth, W T KW - Blood Glucose KW - Cardiovascular Diseases KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Hospitalization KW - Hospitals, Veterans KW - Humans KW - Insurance Claim Review KW - International Classification of Diseases KW - Lipids KW - Male KW - Managed Care Programs KW - Medicare KW - Risk Factors KW - Sampling Studies KW - Treatment Outcome KW - United States AB -

BACKGROUND: 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.

VL - 133 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26538580?dopt=Abstract ER - TY - JOUR T1 - Targeted 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. JF - Hum Mol Genet Y1 - 2016 A1 - Hsu, Yi-Hsiang A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Brody, Jennifer A A1 - Karasik, David A1 - Chou, Wen-Chi A1 - Demissie, Serkalem A1 - Nandakumar, Kannabiran A1 - Zhou, Yanhua A1 - Cheng, Chia-Ho A1 - Gill, Richard A1 - Gibbs, Richard A A1 - Muzny, Donna A1 - Santibanez, Jireh A1 - Estrada, Karol A1 - Rivadeneira, Fernando A1 - Harris, Tamara A1 - Gudnason, Vilmundur A1 - Uitterlinden, Andre A1 - Psaty, Bruce M A1 - Robbins, John A A1 - Adrienne Cupples, L A1 - Kiel, Douglas P AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis. JF - J Clin Endocrinol Metab Y1 - 2016 A1 - Chaker, Layal A1 - Baumgartner, Christine A1 - den Elzen, Wendy P J A1 - Collet, Tinh-Hai A1 - Ikram, M Arfan A1 - Blum, Manuel R A1 - Dehghan, Abbas A1 - Drechsler, Christiane A1 - Luben, Robert N A1 - Portegies, Marileen L P A1 - Iervasi, Giorgio A1 - Medici, Marco A1 - Stott, David J A1 - Dullaart, Robin P A1 - Ford, Ian A1 - Bremner, Alexandra A1 - Newman, Anne B A1 - Wanner, Christoph A1 - Sgarbi, José A A1 - Dörr, Marcus A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Maciel, Rui M B A1 - Westendorp, Rudi G A1 - Jukema, J Wouter A1 - Ceresini, Graziano A1 - Imaizumi, Misa A1 - Hofman, Albert A1 - Bakker, Stephan J L A1 - Franklyn, Jayne A A1 - Khaw, Kay-Tee A1 - Bauer, Douglas C A1 - Walsh, John P A1 - Razvi, Salman A1 - Gussekloo, Jacobijn A1 - Völzke, Henry A1 - Franco, Oscar H A1 - Cappola, Anne R A1 - Rodondi, Nicolas A1 - Peeters, Robin P AB -

CONTEXT: 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.

VL - 101 IS - 11 ER - TY - JOUR T1 - Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. JF - Am J Hum Genet Y1 - 2016 A1 - Liu, Ching-Ti A1 - Raghavan, Sridharan A1 - Maruthur, Nisa A1 - Kabagambe, Edmond Kato A1 - Hong, Jaeyoung A1 - Ng, Maggie C Y A1 - Hivert, Marie-France A1 - Lu, Yingchang A1 - An, Ping A1 - Bentley, Amy R A1 - Drolet, Anne M A1 - Gaulton, Kyle J A1 - Guo, Xiuqing A1 - Armstrong, Loren L A1 - Irvin, Marguerite R A1 - Li, Man A1 - Lipovich, Leonard A1 - Rybin, Denis V A1 - Taylor, Kent D A1 - Agyemang, Charles A1 - Palmer, Nicholette D A1 - Cade, Brian E A1 - Chen, Wei-Min A1 - Dauriz, Marco A1 - Delaney, Joseph A C A1 - Edwards, Todd L A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Lange, Leslie A A1 - Leong, Aaron A1 - Liu, Jingmin A1 - Liu, Yongmei A1 - Nayak, Uma A1 - Patel, Sanjay R A1 - Porneala, Bianca C A1 - Rasmussen-Torvik, Laura J A1 - Snijder, Marieke B A1 - Stallings, Sarah C A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Biggs, Mary L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Chen, Guanjie A1 - Correa, Adolfo A1 - Couper, David J A1 - Crawford, Dana C A1 - Cushman, Mary A1 - Eicher, John D A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fu, Yi-Ping A1 - Goodarzi, Mark O A1 - Gottesman, Omri A1 - Hara, Kazuo A1 - Harris, Tamara B A1 - Jensen, Richard A A1 - Johnson, Andrew D A1 - Jhun, Min A A1 - Karter, Andrew J A1 - Keller, Margaux F A1 - Kho, Abel N A1 - Kizer, Jorge R A1 - Krauss, Ronald M A1 - Langefeld, Carl D A1 - Li, Xiaohui A1 - Liang, Jingling A1 - Liu, Simin A1 - Lowe, William L A1 - Mosley, Thomas H A1 - North, Kari E A1 - Pacheco, Jennifer A A1 - Peyser, Patricia A A1 - Patrick, Alan L A1 - Rice, Kenneth M A1 - Selvin, Elizabeth A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Tajuddin, Salman M A1 - Vaidya, Dhananjay A1 - Wren, Mary P A1 - Yao, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Julie T A1 - Zmuda, Joseph M A1 - Zonderman, Alan B A1 - Zwinderman, Aeilko H A1 - Adeyemo, Adebowale A1 - Boerwinkle, Eric A1 - Ferrucci, Luigi A1 - Hayes, M Geoffrey A1 - Kardia, Sharon L R A1 - Miljkovic, Iva A1 - Pankow, James S A1 - Rotimi, Charles N A1 - Sale, Michèle M A1 - Wagenknecht, Lynne E A1 - Arnett, Donna K A1 - Chen, Yii-Der Ida A1 - Nalls, Michael A A1 - Province, Michael A A1 - Kao, W H Linda A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Loos, Ruth J F A1 - Dupuis, Josée A1 - Rich, Stephen S A1 - Florez, Jose C A1 - Rotter, Jerome I A1 - Morris, Andrew P A1 - Meigs, James B AB -

Knowledge 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.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract ER - TY - JOUR T1 - Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram. JF - Hum Mol Genet Y1 - 2016 A1 - Verweij, Niek A1 - Mateo Leach, Irene A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Bis, Joshua C A1 - Pers, Tune H A1 - van den Berg, Marten E A1 - Lyytikäinen, Leo-Pekka A1 - Barnett, Phil A1 - Wang, Xinchen A1 - Soliman, Elsayed Z A1 - van Duijn, Cornelia M A1 - Kähönen, Mika A1 - van Veldhuisen, Dirk J A1 - Kors, Jan A A1 - Raitakari, Olli T A1 - Silva, Claudia T A1 - Lehtimäki, Terho A1 - Hillege, Hans L A1 - Hirschhorn, Joel N A1 - Boyer, Laurie A A1 - van Gilst, Wiek H A1 - Alonso, Alvaro A1 - Sotoodehnia, Nona A1 - Eijgelsheim, Mark A1 - de Boer, Rudolf A A1 - de Bakker, Paul I W A1 - Franke, Lude A1 - van der Harst, Pim KW - Adaptor Proteins, Signal Transducing KW - Arrhythmias, Cardiac KW - Basic Helix-Loop-Helix Transcription Factors KW - Brugada Syndrome KW - Cardiac Conduction System Disease KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Repressor Proteins KW - Shab Potassium Channels KW - Shal Potassium Channels AB -

The 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.

VL - 25 IS - 10 ER - TY - JOUR T1 - Whole Exome Sequencing in Atrial Fibrillation. JF - PLoS Genet Y1 - 2016 A1 - Lubitz, Steven A A1 - Brody, Jennifer A A1 - Bihlmeyer, Nathan A A1 - Roselli, Carolina A1 - Weng, Lu-Chen A1 - Christophersen, Ingrid E A1 - Alonso, Alvaro A1 - Boerwinkle, Eric A1 - Gibbs, Richard A A1 - Bis, Joshua C A1 - Cupples, L Adrienne A1 - Mohler, Peter J A1 - Nickerson, Deborah A A1 - Muzny, Donna A1 - Perez, Marco V A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Lunetta, Kathryn L A1 - Benjamin, Emelia J A1 - Heckbert, Susan R A1 - Arking, Dan E A1 - Ellinor, Patrick T A1 - Lin, Honghuang AB -

Atrial 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.

VL - 12 IS - 9 ER - TY - JOUR T1 - Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. JF - Am J Hum Genet Y1 - 2016 A1 - Polfus, Linda M A1 - Khajuria, Rajiv K A1 - Schick, Ursula M A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Auer, Paul L A1 - Floyd, James S A1 - Huang, Jie A1 - Lange, Leslie A1 - van Rooij, Frank J A A1 - Gibbs, Richard A A1 - Metcalf, Ginger A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - Walter, Klaudia A1 - Chen, Lu A1 - Yanek, Lisa A1 - Becker, Lewis C A1 - Peloso, Gina M A1 - Wakabayashi, Aoi A1 - Kals, Mart A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Fox, Keolu A1 - Wallace, Robert A1 - Franceschini, Nora A1 - Matijevic, Nena A1 - Rice, Kenneth M A1 - Bartz, Traci M A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Li-Gao, Ruifang A1 - Mook-Kanamori, Dennis O A1 - Lettre, Guillaume A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Soranzo, Nicole A1 - Dehghan, Abbas A1 - Boerwinkle, Eric A1 - Zhang, Xiaoling A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Johnsen, Jill M A1 - Reiner, Alexander P A1 - Ganesh, Santhi K A1 - Sankaran, Vijay G VL - 99 IS - 3 ER - TY - JOUR T1 - Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies. JF - JAMA Cardiol Y1 - 2017 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - Robinson-Cohen, Cassianne A1 - Odden, Michelle C A1 - Dalrymple, Lorien A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Siscovick, David S A1 - Zelnick, Leila A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Correa, Adolfo A1 - Afkarian, Maryam A1 - Young, Bessie A1 - de Boer, Ian H AB -

Importance: 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.

VL - 2 IS - 3 ER - TY - JOUR T1 - The Alzheimer's Disease Sequencing Project: Study design and sample selection. JF - Neurol Genet Y1 - 2017 A1 - Beecham, Gary W A1 - Bis, J C A1 - Martin, E R A1 - Choi, S-H A1 - DeStefano, A L A1 - van Duijn, C M A1 - Fornage, M A1 - Gabriel, S B A1 - Koboldt, D C A1 - Larson, D E A1 - Naj, A C A1 - Psaty, B M A1 - Salerno, W A1 - Bush, W S A1 - Foroud, T M A1 - Wijsman, E A1 - Farrer, L A A1 - Goate, A A1 - Haines, J L A1 - Pericak-Vance, Margaret A A1 - Boerwinkle, E A1 - Mayeux, R A1 - Seshadri, S A1 - Schellenberg, G VL - 3 IS - 5 ER - TY - JOUR T1 - Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. JF - Nat Genet Y1 - 2017 A1 - Brody, Jennifer A A1 - Morrison, Alanna C A1 - Bis, Joshua C A1 - O'Connell, Jeffrey R A1 - Brown, Michael R A1 - Huffman, Jennifer E A1 - Ames, Darren C A1 - Carroll, Andrew A1 - Conomos, Matthew P A1 - Gabriel, Stacey A1 - Gibbs, Richard A A1 - Gogarten, Stephanie M A1 - Gupta, Namrata A1 - Jaquish, Cashell E A1 - Johnson, Andrew D A1 - Lewis, Joshua P A1 - Liu, Xiaoming A1 - Manning, Alisa K A1 - Papanicolaou, George J A1 - Pitsillides, Achilleas N A1 - Rice, Kenneth M A1 - Salerno, William A1 - Sitlani, Colleen M A1 - Smith, Nicholas L A1 - Heckbert, Susan R A1 - Laurie, Cathy C A1 - Mitchell, Braxton D A1 - Vasan, Ramachandran S A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Cupples, L Adrienne VL - 49 IS - 11 ER - TY - JOUR T1 - The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study. JF - J Clin Endocrinol Metab Y1 - 2017 A1 - Aneke-Nash, Chino S A1 - Xue, XiaoNan A1 - Qi, Qibin A1 - Biggs, Mary L A1 - Cappola, Anne A1 - Kuller, Lewis A1 - Pollak, Michael A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Mukamal, Kenneth A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Longitudinal Studies KW - Male KW - New England KW - Prospective Studies KW - Risk AB -

Context: 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.

VL - 102 IS - 12 ER - TY - JOUR T1 - Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. JF - JAMA Oncol Y1 - 2017 A1 - Haycock, Philip C A1 - Burgess, Stephen A1 - Nounu, Aayah A1 - Zheng, Jie A1 - Okoli, George N A1 - Bowden, Jack A1 - Wade, Kaitlin Hazel A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Willeit, Peter A1 - Aviv, Abraham A1 - Gaunt, Tom R A1 - Hemani, Gibran A1 - Mangino, Massimo A1 - Ellis, Hayley Patricia A1 - Kurian, Kathreena M A1 - Pooley, Karen A A1 - Eeles, Rosalind A A1 - Lee, Jeffrey E A1 - Fang, Shenying A1 - Chen, Wei V A1 - Law, Matthew H A1 - Bowdler, Lisa M A1 - Iles, Mark M A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Markus, Hugh Stephen A1 - Hung, Rayjean J A1 - Amos, Chris I A1 - Spurdle, Amanda B A1 - Thompson, Deborah J A1 - O'Mara, Tracy A A1 - Wolpin, Brian A1 - Amundadottir, Laufey A1 - Stolzenberg-Solomon, Rachael A1 - Trichopoulou, Antonia A1 - Onland-Moret, N Charlotte A1 - Lund, Eiliv A1 - Duell, Eric J A1 - Canzian, Federico A1 - Severi, Gianluca A1 - Overvad, Kim A1 - Gunter, Marc J A1 - Tumino, Rosario A1 - Svenson, Ulrika A1 - van Rij, Andre A1 - Baas, Annette F A1 - Bown, Matthew J A1 - Samani, Nilesh J A1 - van t'Hof, Femke N G A1 - Tromp, Gerard A1 - Jones, Gregory T A1 - Kuivaniemi, Helena A1 - Elmore, James R A1 - Johansson, Mattias A1 - Mckay, James A1 - Scelo, Ghislaine A1 - Carreras-Torres, Robert A1 - Gaborieau, Valerie A1 - Brennan, Paul A1 - Bracci, Paige M A1 - Neale, Rachel E A1 - Olson, Sara H A1 - Gallinger, Steven A1 - Li, Donghui A1 - Petersen, Gloria M A1 - Risch, Harvey A A1 - Klein, Alison P A1 - Han, Jiali A1 - Abnet, Christian C A1 - Freedman, Neal D A1 - Taylor, Philip R A1 - Maris, John M A1 - Aben, Katja K A1 - Kiemeney, Lambertus A A1 - Vermeulen, Sita H A1 - Wiencke, John K A1 - Walsh, Kyle M A1 - Wrensch, Margaret A1 - Rice, Terri A1 - Turnbull, Clare A1 - Litchfield, Kevin A1 - Paternoster, Lavinia A1 - Standl, Marie A1 - Abecasis, Goncalo R A1 - SanGiovanni, John Paul A1 - Li, Yong A1 - Mijatovic, Vladan A1 - Sapkota, Yadav A1 - Low, Siew-Kee A1 - Zondervan, Krina T A1 - Montgomery, Grant W A1 - Nyholt, Dale R A1 - van Heel, David A A1 - Hunt, Karen A1 - Arking, Dan E A1 - Ashar, Foram N A1 - Sotoodehnia, Nona A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Comeau, Mary E A1 - Brown, W Mark A1 - Silverman, Edwin K A1 - Hokanson, John E A1 - Cho, Michael H A1 - Hui, Jennie A1 - Ferreira, Manuel A A1 - Thompson, Philip J A1 - Morrison, Alanna C A1 - Felix, Janine F A1 - Smith, Nicholas L A1 - Christiano, Angela M A1 - Petukhova, Lynn A1 - Betz, Regina C A1 - Fan, Xing A1 - Zhang, Xuejun A1 - Zhu, Caihong A1 - Langefeld, Carl D A1 - Thompson, Susan D A1 - Wang, Feijie A1 - Lin, Xu A1 - Schwartz, David A A1 - Fingerlin, Tasha A1 - Rotter, Jerome I A1 - Cotch, Mary Frances A1 - Jensen, Richard A A1 - Munz, Matthias A1 - Dommisch, Henrik A1 - Schaefer, Arne S A1 - Han, Fang A1 - Ollila, Hanna M A1 - Hillary, Ryan P A1 - Albagha, Omar A1 - Ralston, Stuart H A1 - Zeng, Chenjie A1 - Zheng, Wei A1 - Shu, Xiao-Ou A1 - Reis, Andre A1 - Uebe, Steffen A1 - Hüffmeier, Ulrike A1 - Kawamura, Yoshiya A1 - Otowa, Takeshi A1 - Sasaki, Tsukasa A1 - Hibberd, Martin Lloyd A1 - Davila, Sonia A1 - Xie, Gang A1 - Siminovitch, Katherine A1 - Bei, Jin-Xin A1 - Zeng, Yi-Xin A1 - Försti, Asta A1 - Chen, Bowang A1 - Landi, Stefano A1 - Franke, Andre A1 - Fischer, Annegret A1 - Ellinghaus, David A1 - Flores, Carlos A1 - Noth, Imre A1 - Ma, Shwu-Fan A1 - Foo, Jia Nee A1 - Liu, Jianjun A1 - Kim, Jong-Won A1 - Cox, David G A1 - Delattre, Olivier A1 - Mirabeau, Olivier A1 - Skibola, Christine F A1 - Tang, Clara S A1 - Garcia-Barcelo, Merce A1 - Chang, Kai-Ping A1 - Su, Wen-Hui A1 - Chang, Yu-Sun A1 - Martin, Nicholas G A1 - Gordon, Scott A1 - Wade, Tracey D A1 - Lee, Chaeyoung A1 - Kubo, Michiaki A1 - Cha, Pei-Chieng A1 - Nakamura, Yusuke A1 - Levy, Daniel A1 - Kimura, Masayuki A1 - Hwang, Shih-Jen A1 - Hunt, Steven A1 - Spector, Tim A1 - Soranzo, Nicole A1 - Manichaikul, Ani W A1 - Barr, R Graham A1 - Kahali, Bratati A1 - Speliotes, Elizabeth A1 - Yerges-Armstrong, Laura M A1 - Cheng, Ching-Yu A1 - Jonas, Jost B A1 - Wong, Tien Yin A1 - Fogh, Isabella A1 - Lin, Kuang A1 - Powell, John F A1 - Rice, Kenneth A1 - Relton, Caroline L A1 - Martin, Richard M A1 - Davey Smith, George KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Germ-Line Mutation KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Telomere KW - Telomere Homeostasis AB -

Importance: 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.

VL - 3 IS - 5 ER - TY - JOUR T1 - Association of Blood Pressure Trajectory With Mortality, Incident Cardiovascular Disease, and Heart Failure in the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2017 A1 - Smitson, Christopher C A1 - Scherzer, Rebecca A1 - Shlipak, Michael G A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Sarnak, Mark J A1 - Odden, Michelle C A1 - Peralta, Carmen A AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Association of Holter-Derived Heart Rate Variability Parameters With the Development of Congestive Heart Failure in the Cardiovascular Health Study. JF - JACC Heart Fail Y1 - 2017 A1 - Patel, Vaiibhav N A1 - Pierce, Brian R A1 - Bodapati, Rohan K A1 - Brown, David L A1 - Ives, Diane G A1 - Stein, Phyllis K AB -

OBJECTIVES: 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.

ER - TY - JOUR T1 - Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. JF - JAMA Cardiol Y1 - 2017 A1 - Ashar, Foram N A1 - Zhang, Yiyi A1 - Longchamps, Ryan J A1 - Lane, John A1 - Moes, Anna A1 - Grove, Megan L A1 - Mychaleckyj, Josyf C A1 - Taylor, Kent D A1 - Coresh, Josef A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Pankratz, Nathan A1 - Guallar, Eliseo A1 - Arking, Dan E AB -

Importance: 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.

VL - 2 IS - 11 ER - TY - JOUR T1 - Atrial ectopy as a mediator of the association between race and atrial fibrillation. JF - Heart Rhythm Y1 - 2017 A1 - Christensen, Matthew A A1 - Nguyen, Kaylin T A1 - Stein, Phyllis K A1 - Fohtung, Raymond B A1 - Soliman, Elsayed Z A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: 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.

VL - 14 IS - 12 ER - TY - JOUR T1 - Automatic identification of variables in epidemiological datasets using logic regression. JF - BMC Med Inform Decis Mak Y1 - 2017 A1 - Lorenz, Matthias W A1 - Abdi, Negin Ashtiani A1 - Scheckenbach, Frank A1 - Pflug, Anja A1 - Bülbül, Alpaslan A1 - Catapano, Alberico L A1 - Agewall, Stefan A1 - Ezhov, Marat A1 - Bots, Michiel L A1 - Kiechl, Stefan A1 - Orth, Andreas AB -

BACKGROUND: 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.

VL - 17 IS - 1 ER - TY - JOUR T1 - Blood Pressure and Heart Rate Measures Associated With Increased Risk of Covert Brain Infarction and Worsening Leukoaraiosis in Older Adults. JF - Arterioscler Thromb Vasc Biol Y1 - 2017 A1 - Leung, Lester Y A1 - Bartz, Traci M A1 - Rice, Kenneth A1 - Floyd, James A1 - Psaty, Bruce A1 - Gutierrez, Jose A1 - Longstreth, W T A1 - Mukamal, Kenneth J KW - Age Factors KW - Aged KW - Antihypertensive Agents KW - Blood Pressure KW - Cerebral Infarction KW - Disease Progression KW - Female KW - Heart Rate KW - Humans KW - Hypertension KW - Incidence KW - Leukoaraiosis KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Prospective Studies KW - Pulsatile Flow KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: 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.

VL - 37 IS - 8 ER - TY - JOUR T1 - Comparing methods to address bias in observational data: statin use and cardiovascular events in a US cohort. JF - Int J Epidemiol Y1 - 2017 A1 - Kaiser, Paulina A1 - Arnold, Alice M A1 - Benkeser, David A1 - Zeki Al Hazzouri, Adina A1 - Hirsch, Calvin H A1 - Psaty, Bruce M A1 - Odden, Michelle C AB -

Background: 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.

ER - TY - JOUR T1 - Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. JF - PLoS One Y1 - 2017 A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Ahluwalia, Tarunveer S A1 - Teumer, Alexander A1 - Kleber, Marcus E A1 - Chen, Ming-Huei A1 - Wang, Jie Jin A1 - Attia, John R A1 - Marioni, Riccardo E A1 - Steri, Maristella A1 - Weng, Lu-Chen A1 - Pool, Rene A1 - Grossmann, Vera A1 - Brody, Jennifer A A1 - Venturini, Cristina A1 - Tanaka, Toshiko A1 - Rose, Lynda M A1 - Oldmeadow, Christopher A1 - Mazur, Johanna A1 - Basu, Saonli A1 - Frånberg, Mattias A1 - Yang, Qiong A1 - Ligthart, Symen A1 - Hottenga, Jouke J A1 - Rumley, Ann A1 - Mulas, Antonella A1 - de Craen, Anton J M A1 - Grotevendt, Anne A1 - Taylor, Kent D A1 - Delgado, Graciela E A1 - Kifley, Annette A1 - Lopez, Lorna M A1 - Berentzen, Tina L A1 - Mangino, Massimo A1 - Bandinelli, Stefania A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Tofler, Geoffrey A1 - de Maat, Moniek P M A1 - Draisma, Harmen H M A1 - Lowe, Gordon D A1 - Zoledziewska, Magdalena A1 - Sattar, Naveed A1 - Lackner, Karl J A1 - Völker, Uwe A1 - McKnight, Barbara A1 - Huang, Jie A1 - Holliday, Elizabeth G A1 - McEvoy, Mark A A1 - Starr, John M A1 - Hysi, Pirro G A1 - Hernandez, Dena G A1 - Guan, Weihua A1 - Rivadeneira, Fernando A1 - McArdle, Wendy L A1 - Slagboom, P Eline A1 - Zeller, Tanja A1 - Psaty, Bruce M A1 - Uitterlinden, André G A1 - de Geus, Eco J C A1 - Stott, David J A1 - Binder, Harald A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Rotter, Jerome I A1 - Ferrucci, Luigi A1 - Spector, Tim D A1 - Deary, Ian J A1 - März, Winfried A1 - Greinacher, Andreas A1 - Wild, Philipp S A1 - Cucca, Francesco A1 - Boomsma, Dorret I A1 - Watkins, Hugh A1 - Tang, Weihong A1 - Ridker, Paul M A1 - Jukema, Jan W A1 - Scott, Rodney J A1 - Mitchell, Paul A1 - Hansen, Torben A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Strachan, David P A1 - Dehghan, Abbas AB -

An 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - The complex genetics of gait speed: genome-wide meta-analysis approach. JF - Aging (Albany NY) Y1 - 2017 A1 - Ben-Avraham, Dan A1 - Karasik, David A1 - Verghese, Joe A1 - Lunetta, Kathryn L A1 - Smith, Jennifer A A1 - Eicher, John D A1 - Vered, Rotem A1 - Deelen, Joris A1 - Arnold, Alice M A1 - Buchman, Aron S A1 - Tanaka, Toshiko A1 - Faul, Jessica D A1 - Nethander, Maria A1 - Fornage, Myriam A1 - Adams, Hieab H A1 - Matteini, Amy M A1 - Callisaya, Michele L A1 - Smith, Albert V A1 - Yu, Lei A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Pattie, Alison A1 - Corley, Janie A1 - Launer, Lenore J A1 - Knopman, Davis S A1 - Parimi, Neeta A1 - Turner, Stephen T A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Gutman, Danielle A1 - Sharvit, Lital A1 - Mooijaart, Simon P A1 - Liewald, David C A1 - Houwing-Duistermaat, Jeanine J A1 - Ohlsson, Claes A1 - Moed, Matthijs A1 - Verlinden, Vincent J A1 - Mellström, Dan A1 - van der Geest, Jos N A1 - Karlsson, Magnus A1 - Hernandez, Dena A1 - McWhirter, Rebekah A1 - Liu, Yongmei A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Weir, David R A1 - Zhao, Wei A1 - Starr, John M A1 - Johnson, Andrew D A1 - Ikram, M Arfan A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Mosley, Thomas H A1 - Srikanth, Velandai K A1 - Windham, Beverly G A1 - Newman, Ann B A1 - Walston, Jeremy D A1 - Davies, Gail A1 - Evans, Daniel S A1 - Slagboom, Eline P A1 - Ferrucci, Luigi A1 - Kiel, Douglas P A1 - Murabito, Joanne M A1 - Atzmon, Gil AB -

Emerging 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults. JF - Am J Epidemiol Y1 - 2017 A1 - Greenlee, Heather A1 - Strizich, Garrett A1 - Lovasi, Gina S A1 - Kaplan, Robert C A1 - Biggs, Mary L A1 - Li, Christopher I A1 - Richardson, John A1 - Burke, Gregory L A1 - Fitzpatrick, Annette L A1 - Fretts, Amanda M A1 - Psaty, Bruce M A1 - Fried, Linda P KW - Aged KW - Aged, 80 and over KW - American Cancer Society KW - American Heart Association KW - Body Mass Index KW - Cardiovascular Diseases KW - Cause of Death KW - Diet KW - Exercise KW - Female KW - Guideline Adherence KW - Healthy Lifestyle KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Neoplasms KW - Practice Guidelines as Topic KW - Prospective Studies KW - United States AB -

Reports 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.

VL - 186 IS - 10 ER - TY - JOUR T1 - Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium. JF - Hum Mol Genet Y1 - 2017 A1 - Jensen, Majken K A1 - Jensen, Richard A A1 - Mukamal, Kenneth J A1 - Guo, Xiuqing A1 - Yao, Jie A1 - Sun, Qi A1 - Cornelis, Marilyn A1 - Liu, Yongmei A1 - Chen, Ming-Huei A1 - Kizer, Jorge R A1 - Djoussé, Luc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Zmuda, Joseph M A1 - Rotter, Jerome I A1 - Garcia, Melissa A1 - Harris, Tamara A1 - Chen, Ida A1 - Goodarzi, Mark O A1 - Nalls, Michael A A1 - Keller, Margaux A1 - Arnold, Alice M A1 - Newman, Anne A1 - Hoogeeven, Ron C A1 - Rexrode, Kathryn M A1 - Rimm, Eric B A1 - Hu, Frank B A1 - Vasan, Ramachandran S A1 - Katz, Ronit A1 - Pankow, James S A1 - Ix, Joachim H AB -

Plasma 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.

ER - TY - JOUR T1 - Discovery 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. JF - PLoS Genet Y1 - 2017 A1 - Ng, Maggie C Y A1 - Graff, Mariaelisa A1 - Lu, Yingchang A1 - Justice, Anne E A1 - Mudgal, Poorva A1 - Liu, Ching-Ti A1 - Young, Kristin A1 - Yanek, Lisa R A1 - Feitosa, Mary F A1 - Wojczynski, Mary K A1 - Rand, Kristin A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Dimitrov, Latchezar A1 - Duan, Qing A1 - Guo, Xiuqing A1 - Lange, Leslie A A1 - Nalls, Michael A A1 - Okut, Hayrettin A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Vedantam, Sailaja A1 - Bradfield, Jonathan P A1 - Chen, Guanjie A1 - Chen, Wei-Min A1 - Chesi, Alessandra A1 - Irvin, Marguerite R A1 - Padhukasahasram, Badri A1 - Smith, Jennifer A A1 - Zheng, Wei A1 - Allison, Matthew A A1 - Ambrosone, Christine B A1 - Bandera, Elisa V A1 - Bartz, Traci M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Blot, William J A1 - Bottinger, Erwin P A1 - Carpten, John A1 - Chanock, Stephen J A1 - Chen, Yii-Der Ida A1 - Conti, David V A1 - Cooper, Richard S A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Garcia, Melissa A1 - Goodman, Phyllis J A1 - Hsu, Yu-Han H A1 - Hu, Jennifer A1 - Huff, Chad D A1 - Ingles, Sue A A1 - John, Esther M A1 - Kittles, Rick A1 - Klein, Eric A1 - Li, Jin A1 - McKnight, Barbara A1 - Nayak, Uma A1 - Nemesure, Barbara A1 - Ogunniyi, Adesola A1 - Olshan, Andrew A1 - Press, Michael F A1 - Rohde, Rebecca A1 - Rybicki, Benjamin A A1 - Salako, Babatunde A1 - Sanderson, Maureen A1 - Shao, Yaming A1 - Siscovick, David S A1 - Stanford, Janet L A1 - Stevens, Victoria L A1 - Stram, Alex A1 - Strom, Sara S A1 - Vaidya, Dhananjay A1 - Witte, John S A1 - Yao, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Regina G A1 - Zonderman, Alan B A1 - Adeyemo, Adebowale A1 - Ambs, Stefan A1 - Cushman, Mary A1 - Faul, Jessica D A1 - Hakonarson, Hakon A1 - Levin, Albert M A1 - Nathanson, Katherine L A1 - Ware, Erin B A1 - Weir, David R A1 - Zhao, Wei A1 - Zhi, Degui A1 - Arnett, Donna K A1 - Grant, Struan F A A1 - Kardia, Sharon L R A1 - Oloapde, Olufunmilayo I A1 - Rao, D C A1 - Rotimi, Charles N A1 - Sale, Michèle M A1 - Williams, L Keoki A1 - Zemel, Babette S A1 - Becker, Diane M A1 - Borecki, Ingrid B A1 - Evans, Michele K A1 - Harris, Tamara B A1 - Hirschhorn, Joel N A1 - Li, Yun A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - North, Kari E AB -

Genome-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.

VL - 13 IS - 4 ER - TY - JOUR T1 - Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations. JF - J Lipid Res Y1 - 2017 A1 - Hu, Yao A1 - Tanaka, Toshiko A1 - Zhu, Jingwen A1 - Guan, Weihua A1 - Wu, Jason H Y A1 - Psaty, Bruce M A1 - McKnight, Barbara A1 - King, Irena B A1 - Sun, Qi A1 - Richard, Melissa A1 - Manichaikul, Ani A1 - Frazier-Wood, Alexis C A1 - Kabagambe, Edmond K A1 - Hopkins, Paul N A1 - Ordovas, Jose M A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Arnett, Donna K A1 - Chen, Yii-der I A1 - Liang, Shuang A1 - Siscovick, David S A1 - Tsai, Michael Y A1 - Rich, Stephen S A1 - Fornage, Myriam A1 - Hu, Frank B A1 - Rimm, Eric B A1 - Jensen, Majken K A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush A1 - Steffen, Lyn M A1 - Morris, Andrew P A1 - Li, Huaixing A1 - Lin, Xu AB -

Monounsaturated 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.

ER - TY - JOUR T1 - Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. JF - BioData Min Y1 - 2017 A1 - Holzinger, Emily R A1 - Verma, Shefali S A1 - Moore, Carrie B A1 - Hall, Molly A1 - De, Rishika A1 - Gilbert-Diamond, Diane A1 - Lanktree, Matthew B A1 - Pankratz, Nathan A1 - Amuzu, Antoinette A1 - Burt, Amber A1 - Dale, Caroline A1 - Dudek, Scott A1 - Furlong, Clement E A1 - Gaunt, Tom R A1 - Kim, Daniel Seung A1 - Riess, Helene A1 - Sivapalaratnam, Suthesh A1 - Tragante, Vinicius A1 - van Iperen, Erik P A A1 - Brautbar, Ariel A1 - Carrell, David S A1 - Crosslin, David R A1 - Jarvik, Gail P A1 - Kuivaniemi, Helena A1 - Kullo, Iftikhar J A1 - Larson, Eric B A1 - Rasmussen-Torvik, Laura J A1 - Tromp, Gerard A1 - Baumert, Jens A1 - Cruickshanks, Karen J A1 - Farrall, Martin A1 - Hingorani, Aroon D A1 - Hovingh, G K A1 - Kleber, Marcus E A1 - Klein, Barbara E A1 - Klein, Ronald A1 - Koenig, Wolfgang A1 - Lange, Leslie A A1 - Mӓrz, Winfried A1 - North, Kari E A1 - Charlotte Onland-Moret, N A1 - Reiner, Alex P A1 - Talmud, Philippa J A1 - van der Schouw, Yvonne T A1 - Wilson, James G A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Moore, Jason H A1 - Drenos, Fotios A1 - Asselbergs, Folkert W A1 - Keating, Brendan J A1 - Ritchie, Marylyn D AB -

BACKGROUND: 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.

VL - 10 ER - TY - JOUR T1 - Discovery of novel heart rate-associated loci using the Exome Chip. JF - Hum Mol Genet Y1 - 2017 A1 - van den Berg, Marten E A1 - Warren, Helen R A1 - Cabrera, Claudia P A1 - Verweij, Niek A1 - Mifsud, Borbala A1 - Haessler, Jeffrey A1 - Bihlmeyer, Nathan A A1 - Fu, Yi-Ping A1 - Weiss, Stefan A1 - Lin, Henry J A1 - Grarup, Niels A1 - Li-Gao, Ruifang A1 - Pistis, Giorgio A1 - Shah, Nabi A1 - Brody, Jennifer A A1 - Müller-Nurasyid, Martina A1 - Lin, Honghuang A1 - Mei, Hao A1 - Smith, Albert V A1 - Lyytikäinen, Leo-Pekka A1 - Hall, Leanne M A1 - van Setten, Jessica A1 - Trompet, Stella A1 - Prins, Bram P A1 - Isaacs, Aaron A1 - Radmanesh, Farid A1 - Marten, Jonathan A1 - Entwistle, Aiman A1 - Kors, Jan A A1 - Silva, Claudia T A1 - Alonso, Alvaro A1 - Bis, Joshua C A1 - de Boer, Rudolf A1 - de Haan, Hugoline G A1 - de Mutsert, Renée A1 - Dedoussis, George A1 - Dominiczak, Anna F A1 - Doney, Alex S F A1 - Ellinor, Patrick T A1 - Eppinga, Ruben N A1 - Felix, Stephan B A1 - Guo, Xiuqing A1 - Hagemeijer, Yanick A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Hwang, Shih-Jen A1 - Kähönen, Mika A1 - Kanters, Jørgen K A1 - Kolcic, Ivana A1 - Launer, Lenore J A1 - Li, Man A1 - Yao, Jie A1 - Linneberg, Allan A1 - Liu, Simin A1 - Macfarlane, Peter W A1 - Mangino, Massimo A1 - Morris, Andrew D A1 - Mulas, Antonella A1 - Murray, Alison D A1 - Nelson, Christopher P A1 - Orrù, Marco A1 - Padmanabhan, Sandosh A1 - Peters, Annette A1 - Porteous, David J A1 - Poulter, Neil A1 - Psaty, Bruce M A1 - Qi, Lihong A1 - Raitakari, Olli T A1 - Rivadeneira, Fernando A1 - Roselli, Carolina A1 - Rudan, Igor A1 - Sattar, Naveed A1 - Sever, Peter A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stanton, Alice V A1 - Stirrups, Kathleen E A1 - Taylor, Kent D A1 - Tobin, Martin D A1 - Uitterlinden, Andre A1 - Vaartjes, Ilonca A1 - Hoes, Arno W A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Xie, Zhijun A1 - Zoledziewska, Magdalena A1 - Tinker, Andrew A1 - Polasek, Ozren A1 - Rosand, Jonathan A1 - Jamshidi, Yalda A1 - van Duijn, Cornelia M A1 - Zeggini, Eleftheria A1 - Wouter Jukema, J A1 - Asselbergs, Folkert W A1 - Samani, Nilesh J A1 - Lehtimäki, Terho A1 - Gudnason, Vilmundur A1 - Wilson, James A1 - Lubitz, Steven A A1 - Kääb, Stefan A1 - Sotoodehnia, Nona A1 - Caulfield, Mark J A1 - Palmer, Colin N A A1 - Sanna, Serena A1 - Mook-Kanamori, Dennis O A1 - Deloukas, Panos A1 - Pedersen, Oluf A1 - Rotter, Jerome I A1 - Dörr, Marcus A1 - O'Donnell, Chris J A1 - Hayward, Caroline A1 - Arking, Dan E A1 - Kooperberg, Charles A1 - van der Harst, Pim A1 - Eijgelsheim, Mark A1 - Stricker, Bruno H A1 - Munroe, Patricia B AB -

Background 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.

ER - TY - JOUR T1 - DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. JF - Am J Hum Genet Y1 - 2017 A1 - Richard, Melissa A A1 - Huan, Tianxiao A1 - Ligthart, Symen A1 - Gondalia, Rahul A1 - Jhun, Min A A1 - Brody, Jennifer A A1 - Irvin, Marguerite R A1 - Marioni, Riccardo A1 - Shen, Jincheng A1 - Tsai, Pei-Chien A1 - Montasser, May E A1 - Jia, Yucheng A1 - Syme, Catriona A1 - Salfati, Elias L A1 - Boerwinkle, Eric A1 - Guan, Weihua A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Morrison, Alanna C A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Uitterlinden, André G A1 - van Meurs, Joyce B A1 - Franco, Oscar H A1 - Zhang, Guosheng A1 - Li, Yun A1 - Stewart, James D A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Chen, Yii-Der Ida A1 - Kardia, Sharon L R A1 - Zhao, Wei A1 - Turner, Stephen T A1 - Absher, Devin A1 - Aslibekyan, Stella A1 - Starr, John M A1 - McRae, Allan F A1 - Hou, Lifang A1 - Just, Allan C A1 - Schwartz, Joel D A1 - Vokonas, Pantel S A1 - Menni, Cristina A1 - Spector, Tim D A1 - Shuldiner, Alan A1 - Damcott, Coleen M A1 - Rotter, Jerome I A1 - Palmas, Walter A1 - Liu, Yongmei A1 - Paus, Tomáš A1 - Horvath, Steve A1 - O'Connell, Jeffrey R A1 - Guo, Xiuqing A1 - Pausova, Zdenka A1 - Assimes, Themistocles L A1 - Sotoodehnia, Nona A1 - Smith, Jennifer A A1 - Arnett, Donna K A1 - Deary, Ian J A1 - Baccarelli, Andrea A A1 - Bell, Jordana T A1 - Whitsel, Eric A1 - Dehghan, Abbas A1 - Levy, Daniel A1 - Fornage, Myriam KW - Aged KW - Blood Pressure KW - CpG Islands KW - Cross-Sectional Studies KW - DNA Methylation KW - Epigenesis, Genetic KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Mendelian Randomization Analysis KW - Middle Aged KW - Nerve Tissue Proteins KW - Quantitative Trait Loci KW - Tetraspanins AB -

Genome-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.

VL - 101 IS - 6 ER - TY - JOUR T1 - Ectopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community. JF - J Am Heart Assoc Y1 - 2017 A1 - Nguyen, Kaylin T A1 - Vittinghoff, Eric A1 - Dewland, Thomas A A1 - Dukes, Jonathan W A1 - Soliman, Elsayed Z A1 - Stein, Phyllis K A1 - Gottdiener, John S A1 - Alonso, Alvaro A1 - Chen, Lin Y A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: 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.

VL - 6 IS - 8 ER - TY - JOUR T1 - Exome-wide association study of plasma lipids in >300,000 individuals. JF - Nat Genet Y1 - 2017 A1 - Liu, Dajiang J A1 - Peloso, Gina M A1 - Yu, Haojie A1 - Butterworth, Adam S A1 - Wang, Xiao A1 - Mahajan, Anubha A1 - Saleheen, Danish A1 - Emdin, Connor A1 - Alam, Dewan A1 - Alves, Alexessander Couto A1 - Amouyel, Philippe A1 - Di Angelantonio, Emanuele A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Baber, Usman A1 - Ballantyne, Christie M A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bis, Joshua C A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brandslund, Ivan A1 - Brown, Morris A1 - Busonero, Fabio A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Y Eugene A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Connell, John M A1 - Cucca, Francesco A1 - Cupples, L Adrienne A1 - Damrauer, Scott M A1 - Davies, Gail A1 - Deary, Ian J A1 - Dedoussis, George A1 - Denny, Joshua C A1 - Dominiczak, Anna A1 - Dubé, Marie-Pierre A1 - Ebeling, Tapani A1 - Eiriksdottir, Gudny A1 - Esko, Tõnu A1 - Farmaki, Aliki-Eleni A1 - Feitosa, Mary F A1 - Ferrario, Marco A1 - Ferrieres, Jean A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frayling, Timothy M A1 - Frikke-Schmidt, Ruth A1 - Fritsche, Lars G A1 - Frossard, Philippe A1 - Fuster, Valentin A1 - Ganesh, Santhi K A1 - Gao, Wei A1 - Garcia, Melissa E A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Grarup, Niels A1 - Groop, Leif A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hirschhorn, Joel N A1 - Holmen, Oddgeir L A1 - Huffman, Jennifer A1 - Huo, Yong A1 - Hveem, Kristian A1 - Jabeen, Sehrish A1 - Jackson, Anne U A1 - Jakobsdottir, Johanna A1 - Jarvelin, Marjo-Riitta A1 - Jensen, Gorm B A1 - Jørgensen, Marit E A1 - Jukema, J Wouter A1 - Justesen, Johanne M A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Khera, Amit V A1 - Klarin, Derek A1 - Koistinen, Heikki A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A1 - Langenberg, Claudia A1 - Langsted, Anne A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Liewald, David C M A1 - Lin, Li An A1 - Linneberg, Allan A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lu, Xiangfeng A1 - Mägi, Reedik A1 - Mälarstig, Anders A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mäntyselkä, Pekka A1 - Marouli, Eirini A1 - Masca, Nicholas G D A1 - Maschio, Andrea A1 - Meigs, James B A1 - Melander, Olle A1 - Metspalu, Andres A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Mulas, Antonella A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Neville, Matt J A1 - Nielsen, Jonas B A1 - Nielsen, Sune F A1 - Nordestgaard, Børge G A1 - Ordovas, Jose M A1 - Mehran, Roxana A1 - O'Donnell, Christoper J A1 - Orho-Melander, Marju A1 - Molony, Cliona M A1 - Muntendam, Pieter A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasko, Dorota A1 - Patel, Aniruddh P A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Pisinger, Charlotta A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil R A1 - Roden, Dan M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sanna, Serena A1 - Sattar, Naveed A1 - Schmidt, Ellen M A1 - Scott, Robert A A1 - Sever, Peter A1 - Sevilla, Raquel S A1 - Shaffer, Christian M A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert V A1 - Smith, Blair H A1 - Somayajula, Sangeetha A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Stirrups, Kathleen E A1 - Stitziel, Nathan A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Surendran, Praveen A1 - Tada, Hayato A1 - Tall, Alan R A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Trompet, Stella A1 - Tsao, Philip S A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - van Zuydam, Natalie R A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Virtamo, Jarmo A1 - Waldenberger, Melanie A1 - Wang, Nan A1 - Wareham, Nick J A1 - Warren, Helen R A1 - Weeke, Peter E A1 - Weinstock, Joshua A1 - Wessel, Jennifer A1 - Wilson, James G A1 - Wilson, Peter W F A1 - Xu, Ming A1 - Yaghootkar, Hanieh A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhang, He A1 - Zheng, Neil S A1 - Zhang, Weihua A1 - Zhang, Yan A1 - Zhou, Wei A1 - Zhou, Yanhua A1 - Zoledziewska, Magdalena A1 - Howson, Joanna M M A1 - Danesh, John A1 - McCarthy, Mark I A1 - Cowan, Chad A A1 - Abecasis, Goncalo A1 - Deloukas, Panos A1 - Musunuru, Kiran A1 - Willer, Cristen J A1 - Kathiresan, Sekar KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Lipids KW - Macular Degeneration KW - Phenotype KW - Risk Factors AB -

We 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.

VL - 49 IS - 12 ER - TY - JOUR T1 - Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function. JF - J Clin Endocrinol Metab Y1 - 2017 A1 - Zaheer, Sarah A1 - de Boer, Ian H A1 - Allison, Matthew A1 - Brown, Jenifer M A1 - Psaty, Bruce M A1 - Robinson-Cohen, Cassianne A1 - Michos, Erin D A1 - Ix, Joachim H A1 - Kestenbaum, Bryan A1 - Siscovick, David A1 - Vaidya, Anand KW - Adiposity KW - Aged KW - Aged, 80 and over KW - Cross-Sectional Studies KW - Female KW - Fibroblast Growth Factors KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Male KW - Middle Aged KW - Minerals KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

Context: 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.

VL - 102 IS - 4 ER - TY - JOUR T1 - Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Magnani, Jared W A1 - Yin, Xiaoyan A1 - Barnard, John A1 - Weng, Lu-Chen A1 - Arking, Dan E A1 - Niemeijer, Maartje N A1 - Lubitz, Steven A A1 - Avery, Christy L A1 - Duan, Qing A1 - Felix, Stephan B A1 - Bis, Joshua C A1 - Kerr, Kathleen F A1 - Isaacs, Aaron A1 - Müller-Nurasyid, Martina A1 - Müller, Christian A1 - North, Kari E A1 - Reiner, Alex P A1 - Tinker, Lesley F A1 - Kors, Jan A A1 - Teumer, Alexander A1 - Petersmann, Astrid A1 - Sinner, Moritz F A1 - Bůzková, Petra A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Meitinger, Thomas A1 - Limacher, Marian C A1 - Wilhelmsen, Kirk C A1 - Psaty, Bruce M A1 - Hofman, Albert A1 - Uitterlinden, Andre A1 - Krijthe, Bouwe P A1 - Zhang, Zhu-Ming A1 - Schnabel, Renate B A1 - Kääb, Stefan A1 - van Duijn, Cornelia A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Dörr, Marcus A1 - Li, Yun A1 - Chung, Mina K A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Whitsel, Eric A A1 - Stricker, Bruno H A1 - Benjamin, Emelia J A1 - Heckbert, Susan R A1 - Ellinor, Patrick T KW - Arrhythmias, Cardiac KW - Caveolin 1 KW - Caveolin 2 KW - Electrocardiography KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Heart Atria KW - Humans KW - NAV1.5 Voltage-Gated Sodium Channel KW - NAV1.8 Voltage-Gated Sodium Channel KW - T-Box Domain Proteins AB -

BACKGROUND: 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.

VL - 10 IS - 4 ER - TY - JOUR T1 - Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. JF - Heart Rhythm Y1 - 2017 A1 - Avery, Christy L A1 - Wassel, Christina L A1 - Richard, Melissa A A1 - Highland, Heather M A1 - Bien, Stephanie A1 - Zubair, Niha A1 - Soliman, Elsayed Z A1 - Fornage, Myriam A1 - Bielinski, Suzette J A1 - Tao, Ran A1 - Seyerle, Amanda A A1 - Shah, Sanjiv J A1 - Lloyd-Jones, Donald M A1 - Buyske, Steven A1 - Rotter, Jerome I A1 - Post, Wendy S A1 - Rich, Stephen S A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Lin, Dan Yu A1 - Whitsel, Eric A A1 - Peters, Ulrike A1 - Haiman, Christopher A A1 - Crawford, Dana C A1 - Kooperberg, Charles A1 - North, Kari E AB -

BACKGROUND: 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.

VL - 14 IS - 4 ER - TY - JOUR T1 - Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. JF - Int J Obes (Lond) Y1 - 2017 A1 - Yoneyama, S A1 - Yao, J A1 - Guo, X A1 - Fernandez-Rhodes, L A1 - Lim, U A1 - Boston, J A1 - Bůžková, P A1 - Carlson, C S A1 - Cheng, I A1 - Cochran, B A1 - Cooper, R A1 - Ehret, G A1 - Fornage, M A1 - Gong, J A1 - Gross, M A1 - Gu, C C A1 - Haessler, J A1 - Haiman, C A A1 - Henderson, B A1 - Hindorff, L A A1 - Houston, D A1 - Irvin, M R A1 - Jackson, R A1 - Kuller, L A1 - Leppert, M A1 - Lewis, C E A1 - Li, R A1 - Le Marchand, L A1 - Matise, T C A1 - Nguyen, K-Dh A1 - Chakravarti, A A1 - Pankow, J S A1 - Pankratz, N A1 - Pooler, L A1 - Ritchie, M D A1 - Bien, S A A1 - Wassel, C L A1 - Chen, Y-DI A1 - Taylor, K D A1 - Allison, M A1 - Rotter, J I A1 - Schreiner, P J A1 - Schumacher, F A1 - Wilkens, L A1 - Boerwinkle, E A1 - Kooperberg, C A1 - Peters, U A1 - Buyske, S A1 - Graff, M A1 - North, K E AB -

BACKGROUND/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.

VL - 41 IS - 2 ER - TY - JOUR T1 - Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. JF - Sci Rep Y1 - 2017 A1 - Weng, Lu-Chen A1 - Lunetta, Kathryn L A1 - Müller-Nurasyid, Martina A1 - Smith, Albert Vernon A1 - Thériault, Sébastien A1 - Weeke, Peter E A1 - Barnard, John A1 - Bis, Joshua C A1 - Lyytikäinen, Leo-Pekka A1 - Kleber, Marcus E A1 - Martinsson, Andreas A1 - Lin, Henry J A1 - Rienstra, Michiel A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Dörr, Marcus A1 - Klarin, Derek A1 - Chasman, Daniel I A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Paré, Guillaume A1 - Teixeira, Pedro L A1 - Denny, Joshua C A1 - Shoemaker, M Benjamin A1 - Van Wagoner, David R A1 - Smith, Jonathan D A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - Kähönen, Mika A1 - Nikus, Kjell A1 - Delgado, Graciela E A1 - Melander, Olle A1 - Engström, Gunnar A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Christophersen, Ingrid E A1 - Ellinor, Patrick T A1 - Geelhoed, Bastiaan A1 - Verweij, Niek A1 - Macfarlane, Peter A1 - Ford, Ian A1 - Heeringa, Jan A1 - Franco, Oscar H A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Teumer, Alexander A1 - Rose, Lynda M A1 - Kääb, Stefan A1 - Gudnason, Vilmundur A1 - Arking, Dan E A1 - Conen, David A1 - Roden, Dan M A1 - Chung, Mina K A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Lehtimäki, Terho A1 - März, Winfried A1 - Smith, J Gustav A1 - Rotter, Jerome I A1 - van der Harst, Pim A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Felix, Stephan B A1 - Albert, Christine M A1 - Lubitz, Steven A AB -

It 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.

VL - 7 IS - 1 ER - TY - JOUR T1 - Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. JF - Nat Genet Y1 - 2017 A1 - Hobbs, Brian D A1 - de Jong, Kim A1 - Lamontagne, Maxime A1 - Bossé, Yohan A1 - Shrine, Nick A1 - Artigas, Maria Soler A1 - Wain, Louise V A1 - Hall, Ian P A1 - Jackson, Victoria E A1 - Wyss, Annah B A1 - London, Stephanie J A1 - North, Kari E A1 - Franceschini, Nora A1 - Strachan, David P A1 - Beaty, Terri H A1 - Hokanson, John E A1 - Crapo, James D A1 - Castaldi, Peter J A1 - Chase, Robert P A1 - Bartz, Traci M A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Gharib, Sina A A1 - Zanen, Pieter A1 - Lammers, Jan W A1 - Oudkerk, Matthijs A1 - Groen, H J A1 - Locantore, Nicholas A1 - Tal-Singer, Ruth A1 - Rennard, Stephen I A1 - Vestbo, Jørgen A1 - Timens, Wim A1 - Paré, Peter D A1 - Latourelle, Jeanne C A1 - Dupuis, Josée A1 - O'Connor, George T A1 - Wilk, Jemma B A1 - Kim, Woo Jin A1 - Lee, Mi Kyeong A1 - Oh, Yeon-Mok A1 - Vonk, Judith M A1 - de Koning, Harry J A1 - Leng, Shuguang A1 - Belinsky, Steven A A1 - Tesfaigzi, Yohannes A1 - Manichaikul, Ani A1 - Wang, Xin-Qun A1 - Rich, Stephen S A1 - Barr, R Graham A1 - Sparrow, David A1 - Litonjua, Augusto A A1 - Bakke, Per A1 - Gulsvik, Amund A1 - Lahousse, Lies A1 - Brusselle, Guy G A1 - Stricker, Bruno H A1 - Uitterlinden, André G A1 - Ampleford, Elizabeth J A1 - Bleecker, Eugene R A1 - Woodruff, Prescott G A1 - Meyers, Deborah A A1 - Qiao, Dandi A1 - Lomas, David A A1 - Yim, Jae-Joon A1 - Kim, Deog Kyeom A1 - Hawrylkiewicz, Iwona A1 - Sliwinski, Pawel A1 - Hardin, Megan A1 - Fingerlin, Tasha E A1 - Schwartz, David A A1 - Postma, Dirkje S A1 - MacNee, William A1 - Tobin, Martin D A1 - Silverman, Edwin K A1 - Boezen, H Marike A1 - Cho, Michael H AB -

Chronic 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.

VL - 49 IS - 3 ER - TY - JOUR T1 - Genetic loci associated with heart rate variability and their effects on cardiac disease risk. JF - Nat Commun Y1 - 2017 A1 - Nolte, Ilja M A1 - Munoz, M Loretto A1 - Tragante, Vinicius A1 - Amare, Azmeraw T A1 - Jansen, Rick A1 - Vaez, Ahmad A1 - von der Heyde, Benedikt A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Dierckx, Bram A1 - van Dongen, Jenny A1 - Gogarten, Stephanie M A1 - Goyette, Philippe A1 - Hernesniemi, Jussi A1 - Huikari, Ville A1 - Hwang, Shih-Jen A1 - Jaju, Deepali A1 - Kerr, Kathleen F A1 - Kluttig, Alexander A1 - Krijthe, Bouwe P A1 - Kumar, Jitender A1 - van der Laan, Sander W A1 - Lyytikäinen, Leo-Pekka A1 - Maihofer, Adam X A1 - Minassian, Arpi A1 - van der Most, Peter J A1 - Müller-Nurasyid, Martina A1 - Nivard, Michel A1 - Salvi, Erika A1 - Stewart, James D A1 - Thayer, Julian F A1 - Verweij, Niek A1 - Wong, Andrew A1 - Zabaneh, Delilah A1 - Zafarmand, Mohammad H A1 - Abdellaoui, Abdel A1 - Albarwani, Sulayma A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ashar, Foram A1 - Auvinen, Juha A1 - Axelsson, Tomas A1 - Baker, Dewleen G A1 - de Bakker, Paul I W A1 - Barcella, Matteo A1 - Bayoumi, Riad A1 - Bieringa, Rob J A1 - Boomsma, Dorret A1 - Boucher, Gabrielle A1 - Britton, Annie R A1 - Christophersen, Ingrid A1 - Dietrich, Andrea A1 - Ehret, George B A1 - Ellinor, Patrick T A1 - Eskola, Markku A1 - Felix, Janine F A1 - Floras, John S A1 - Franco, Oscar H A1 - Friberg, Peter A1 - Gademan, Maaike G J A1 - Geyer, Mark A A1 - Giedraitis, Vilmantas A1 - Hartman, Catharina A A1 - Hemerich, Daiane A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huikuri, Heikki A1 - Hutri-Kähönen, Nina A1 - Jouven, Xavier A1 - Junttila, Juhani A1 - Juonala, Markus A1 - Kiviniemi, Antti M A1 - Kors, Jan A A1 - Kumari, Meena A1 - Kuznetsova, Tatiana A1 - Laurie, Cathy C A1 - Lefrandt, Joop D A1 - Li, Yong A1 - Li, Yun A1 - Liao, Duanping A1 - Limacher, Marian C A1 - Lin, Henry J A1 - Lindgren, Cecilia M A1 - Lubitz, Steven A A1 - Mahajan, Anubha A1 - McKnight, Barbara A1 - Zu Schwabedissen, Henriette Meyer A1 - Milaneschi, Yuri A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Nalls, Mike A A1 - Navis, Gerjan A1 - Neijts, Melanie A1 - Nikus, Kjell A1 - North, Kari E A1 - O'Connor, Daniel T A1 - Ormel, Johan A1 - Perz, Siegfried A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Risbrough, Victoria B A1 - Sinner, Moritz F A1 - Siscovick, David A1 - Smit, Johannes H A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Staessen, Jan A A1 - Stein, Phyllis K A1 - Stilp, Adrienne M A1 - Stolarz-Skrzypek, Katarzyna A1 - Strauch, Konstantin A1 - Sundström, Johan A1 - Swenne, Cees A A1 - Syvänen, Ann-Christine A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tinker, Lesley E A1 - Uitterlinden, André G A1 - van Setten, Jessica A1 - Voss, Andreas A1 - Waldenberger, Melanie A1 - Wilhelmsen, Kirk C A1 - Willemsen, Gonneke A1 - Wong, Quenna A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Cusi, Daniele A1 - Evans, Michele K A1 - Greiser, Halina K A1 - van der Harst, Pim A1 - Hassan, Mohammad A1 - Ingelsson, Erik A1 - Jarvelin, Marjo-Riitta A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kivimaki, Mika A1 - Kooperberg, Charles A1 - Kuh, Diana A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Nievergelt, Caroline M A1 - O'Donnell, Chris J A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda A1 - Reiner, Alexander P A1 - Riese, Harriëtte A1 - van Roon, Arie M A1 - Rioux, John D A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Stricker, Bruno H A1 - Tiemeier, Henning A1 - Vrijkotte, Tanja G M A1 - Asselbergs, Folkert W A1 - Brundel, Bianca J J M A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - den Hoed, Marcel A1 - Snieder, Harold A1 - de Geus, Eco J C AB -

Reduced 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 (-0.74 VL - 8 ER - TY - JOUR T1 - {Genetic Risk Prediction of Atrial Fibrillation JF - Circulation Y1 - 2017 A1 - Lubitz, S. A. A1 - Yin, X. A1 - Lin, H. J. A1 - Kolek, M. A1 - Smith, J. G. A1 - Trompet, S. A1 - Rienstra, M. A1 - Rost, N. S. A1 - Teixeira, P. L. A1 - Almgren, P. A1 - Anderson, C. D. A1 - Chen, L. Y. A1 - Engstr?m, G. A1 - Ford, I. A1 - Furie, K. L. A1 - Guo, X. A1 - Larson, M. G. A1 - Lunetta, K. L. A1 - Macfarlane, P. W. A1 - Psaty, B. M. A1 - Soliman, E. Z. A1 - Sotoodehnia, N. A1 - Stott, D. J. A1 - Taylor, K. D. A1 - Weng, L. C. A1 - Yao, J. A1 - Geelhoed, B. A1 - Verweij, N. A1 - Siland, J. E. A1 - Kathiresan, S. A1 - Roselli, C. A1 - Roden, D. M. A1 - van der Harst, P. A1 - Darbar, D. A1 - Jukema, J. W. A1 - Melander, O. A1 - Rosand, J. A1 - Rotter, J. I. A1 - Heckbert, S. R. A1 - Ellinor, P. T. A1 - Alonso, A. A1 - Benjamin, E. J. AB - Atrial 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. VL - 135 ER - TY - JOUR T1 - Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study. JF - Diabetes Y1 - 2017 A1 - Sobrin, Lucia A1 - Chong, Yong He A1 - Fan, Qiao A1 - Gan, Alfred A1 - Stanwyck, Lynn K A1 - Kaidonis, Georgia A1 - Craig, Jamie E A1 - Kim, Jihye A1 - Liao, Wen-Ling A1 - Huang, Yu-Chuen A1 - Lee, Wen-Jane A1 - Hung, Yi-Jen A1 - Guo, Xiuqing A1 - Hai, Yang A1 - Ipp, Eli A1 - Pollack, Samuela A1 - Hancock, Heather A1 - Price, Alkes A1 - Penman, Alan A1 - Mitchell, Paul A1 - Liew, Gerald A1 - Smith, Albert V A1 - Gudnason, Vilmundur A1 - Tan, Gavin A1 - Klein, Barbara E K A1 - Kuo, Jane A1 - Li, Xiaohui A1 - Christiansen, Mark W A1 - Psaty, Bruce M A1 - Sandow, Kevin A1 - Jensen, Richard A A1 - Klein, Ronald A1 - Cotch, Mary Frances A1 - Wang, Jie Jin A1 - Jia, Yucheng A1 - Chen, Ching J A1 - Chen, Yii-Der Ida A1 - Rotter, Jerome I A1 - Tsai, Fuu-Jen A1 - Hanis, Craig L A1 - Burdon, Kathryn P A1 - Wong, Tien Yin A1 - Cheng, Ching-Yu KW - Aged KW - Diabetic Retinopathy KW - Female KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk AB -

Results 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.

VL - 66 IS - 12 ER - TY - JOUR T1 - {Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk JF - Nat Genet Y1 - 2017 A1 - Warren, H. R. A1 - Evangelou, E. A1 - Cabrera, C. P. A1 - Gao, H. A1 - Ren, M. A1 - Mifsud, B. A1 - Ntalla, I. A1 - Surendran, P. A1 - Liu, C. A1 - Cook, J. P. A1 - Kraja, A. T. A1 - Drenos, F. A1 - Loh, M. A1 - Verweij, N. A1 - Marten, J. A1 - Karaman, I. A1 - Lepe, M. P. A1 - O'Reilly, P. F. A1 - Knight, J. A1 - Snieder, H. A1 - Kato, N. A1 - He, J. A1 - Tai, E. S. A1 - Said, M. A. A1 - Porteous, D. A1 - Alver, M. A1 - Poulter, N. A1 - Farrall, M. A1 - Gansevoort, R. T. A1 - Padmanabhan, S. A1 - M?gi, R. A1 - Stanton, A. A1 - Connell, J. A1 - Bakker, S. J. A1 - Metspalu, A. A1 - Shields, D. C. A1 - Thom, S. A1 - Brown, M. A1 - Sever, P. A1 - Esko, T. A1 - Hayward, C. A1 - van der Harst, P. A1 - Saleheen, D. A1 - Chowdhury, R. A1 - Chambers, J. C. A1 - Chasman, D. I. A1 - Chakravarti, A. A1 - Newton-Cheh, C. A1 - Lindgren, C. M. A1 - Levy, D. A1 - Kooner, J. S. A1 - Keavney, B. A1 - Tomaszewski, M. A1 - Samani, N. J. A1 - Howson, J. M. A1 - Tobin, M. D. A1 - Munroe, P. B. A1 - Ehret, G. B. A1 - Wain, L. V. A1 - V?lker, U. A1 - Vollenweider, P. A1 - Wild, S. A1 - Willemsen, G. A1 - Wright, A. F. A1 - Yao, J. A1 - Th?riault, S. A1 - Conen, D. A1 - John, A. A1 - Sever, P. A1 - Debette, S. A1 - Mook-Kanamori, D. O. A1 - Zeggini, E. A1 - Spector, T. D. A1 - van der Harst, P. A1 - Palmer, C. N. A1 - Vergnaud, A. C. A1 - Loos, R. J. A1 - Polasek, O. A1 - Starr, J. M. A1 - Girotto, G. A1 - Hayward, C. A1 - Kooner, J. S. A1 - Lindgren, C. M. A1 - Vitart, V. A1 - Samani, N. J. A1 - Tuomilehto, J. A1 - Gyllensten, U. A1 - Knekt, P. A1 - Deary, I. J. A1 - Ciullo, M. A1 - Elosua, R. A1 - Keavney, B. D. A1 - Hicks, A. A. A1 - Scott, R. A. A1 - Gasparini, P. A1 - Laan, M. A1 - Liu, Y. A1 - Watkins, H. A1 - Hartman, C. A. A1 - Salomaa, V. A1 - Toniolo, D. A1 - Perola, M. A1 - Wilson, J. F. A1 - Schmidt, H. A1 - Zhao, J. H. A1 - Lehtim?ki, T. A1 - van Duijn, C. M. A1 - Gudnason, V. A1 - Psaty, B. M. A1 - Peters, A. A1 - Rettig, R. A1 - James, A. A1 - Jukema, J. W. A1 - Strachan, D. P. A1 - Palmas, W. A1 - Metspalu, A. A1 - Ingelsson, E. A1 - Boomsma, D. I. A1 - Franco, O. H. A1 - Bochud, M. A1 - Newton-Cheh, C. A1 - Munroe, P. B. A1 - Elliott, P. A1 - Chasman, D. I. A1 - Chakravarti, A. A1 - Knight, J. A1 - Morris, A. P. A1 - Levy, D. A1 - Tobin, M. D. A1 - Snieder, H. A1 - Caulfield, M. J. A1 - Ehret, G. B. A1 - Barnes, M. R. A1 - Tzoulaki, I. A1 - Caulfield, M. J. A1 - Elliott, P. AB - Elevated 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. VL - 49 ER - TY - JOUR T1 - Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. JF - PLoS One Y1 - 2017 A1 - Mozaffarian, Dariush A1 - Dashti, Hassan S A1 - Wojczynski, Mary K A1 - Chu, Audrey Y A1 - Nettleton, Jennifer A A1 - Männistö, Satu A1 - Kristiansson, Kati A1 - Reedik, Mägi A1 - Lahti, Jari A1 - Houston, Denise K A1 - Cornelis, Marilyn C A1 - van Rooij, Frank J A A1 - Dimitriou, Maria A1 - Kanoni, Stavroula A1 - Mikkilä, Vera A1 - Steffen, Lyn M A1 - de Oliveira Otto, Marcia C A1 - Qi, Lu A1 - Psaty, Bruce A1 - Djoussé, Luc A1 - Rotter, Jerome I A1 - Harald, Kennet A1 - Perola, Markus A1 - Rissanen, Harri A1 - Jula, Antti A1 - Krista, Fischer A1 - Mihailov, Evelin A1 - Feitosa, Mary F A1 - Ngwa, Julius S A1 - Xue, Luting A1 - Jacques, Paul F A1 - Perälä, Mia-Maria A1 - Palotie, Aarno A1 - Liu, Yongmei A1 - Nalls, Nike A A1 - Ferrucci, Luigi A1 - Hernandez, Dena A1 - Manichaikul, Ani A1 - Tsai, Michael Y A1 - Kiefte-de Jong, Jessica C A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rallidis, Loukianos A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Buring, Julie E A1 - Lehtimäki, Terho A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lemaitre, Rozenn A1 - Salomaa, Veikko A1 - Knekt, Paul A1 - Metspalu, Andres A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Eriksson, Johan G A1 - Kritchevsky, Stephen B A1 - Bandinelli, Stefania A1 - Siscovick, David A1 - Franco, Oscar H A1 - Deloukas, Panos A1 - Dedoussis, George A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Tanaka, Toshiko KW - Adult KW - Aged KW - Cohort Studies KW - Docosahexaenoic Acids KW - Eicosapentaenoic Acid KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Seafood KW - United States AB -

BACKGROUND: 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.

VL - 12 IS - 12 ER - TY - JOUR T1 - Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Li, Changwei A1 - Kim, Yun Kyoung A1 - Dorajoo, Rajkumar A1 - Li, Huaixing A1 - Lee, I-Te A1 - Cheng, Ching-Yu A1 - He, Meian A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Ganesh, Santhi K A1 - He, Jiang A1 - Lee, Juyoung A1 - Liu, Jianjun A1 - Hu, Yao A1 - Rao, Dabeeru C A1 - Tsai, Fuu-Jen A1 - Koh, Jia Yu A1 - Hu, Hua A1 - Liang, Kae-Woei A1 - Palmas, Walter A1 - Hixson, James E A1 - Han, Sohee A1 - Teo, Yik-Ying A1 - Wang, Yiqin A1 - Chen, Jing A1 - Lu, Chieh Hsiang A1 - Zheng, Yingfeng A1 - Gui, Lixuan A1 - Lee, Wen-Jane A1 - Yao, Jie A1 - Gu, Dongfeng A1 - Han, Bok-Ghee A1 - Sim, Xueling A1 - Sun, Liang A1 - Zhao, Jinying A1 - Chen, Chien-Hsiun A1 - Kumari, Neelam A1 - He, Yunfeng A1 - Taylor, Kent D A1 - Raffel, Leslie J A1 - Moon, Sanghoon A1 - Rotter, Jerome I A1 - Ida Chen, Yii-Der A1 - Wu, Tangchun A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Lin, Xu A1 - Tai, E-Shyong A1 - Kim, Bong-Jo A1 - Kelly, Tanika N KW - Asian Continental Ancestry Group KW - Blood Pressure KW - Far East KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 10 IS - 2 ER - TY - JOUR T1 - A 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. JF - J Med Genet Y1 - 2017 A1 - Noordam, Raymond A1 - Sitlani, Colleen M A1 - Avery, Christy L A1 - Stewart, James D A1 - Gogarten, Stephanie M A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Warren, Helen R A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Li, Xiaohui A1 - Li, Jin A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Busch, Evan L A1 - Caulfield, Mark J A1 - Chen, Yii-der I A1 - Cummings, Steven R A1 - Cupples, L Adrienne A1 - Duan, Qing A1 - Franco, Oscar H A1 - Méndez-Giráldez, Rául A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - van Heemst, Diana A1 - Hofman, Albert A1 - Floyd, James S A1 - Kors, Jan A A1 - Launer, Lenore J A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lange, Leslie A A1 - Lin, Henry J A1 - de Mutsert, Renée A1 - Napier, Melanie D A1 - Newton-Cheh, Christopher A1 - Poulter, Neil A1 - Reiner, Alexander P A1 - Rice, Kenneth M A1 - Roach, Jeffrey A1 - Rodriguez, Carlos J A1 - Rosendaal, Frits R A1 - Sattar, Naveed A1 - Sever, Peter A1 - Seyerle, Amanda A A1 - Slagboom, P Eline A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Thornton, Timothy A A1 - Uitterlinden, André G A1 - Wilhelmsen, Kirk C A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - Jukema, J Wouter A1 - Laurie, Cathy C A1 - Liu, Yongmei A1 - Mook-Kanamori, Dennis O A1 - Munroe, Patricia B A1 - Rotter, Jerome I A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Stricker, Bruno H A1 - Whitsel, Eric A AB -

BACKGROUND: 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.

VL - 54 IS - 5 ER - TY - JOUR T1 - Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent. JF - Mol Nutr Food Res Y1 - 2017 A1 - Smith, Caren E A1 - Follis, Jack L A1 - Dashti, Hassan S A1 - Tanaka, Toshiko A1 - Graff, Mariaelisa A1 - Fretts, Amanda M A1 - Kilpeläinen, Tuomas O A1 - Wojczynski, Mary K A1 - Richardson, Kris A1 - Nalls, Mike A A1 - Schulz, Christina-Alexandra A1 - Liu, Yongmei A1 - Frazier-Wood, Alexis C A1 - van Eekelen, Esther A1 - Wang, Carol A1 - de Vries, Paul S A1 - Mikkilä, Vera A1 - Rohde, Rebecca A1 - Psaty, Bruce M A1 - Hansen, Torben A1 - Feitosa, Mary F A1 - Lai, Chao-Qiang A1 - Houston, Denise K A1 - Ferruci, Luigi A1 - Ericson, Ulrika A1 - Wang, Zhe A1 - de Mutsert, Renée A1 - Oddy, Wendy H A1 - de Jonge, Ester A L A1 - Seppälä, Ilkka A1 - Justice, Anne E A1 - Lemaitre, Rozenn N A1 - Sørensen, Thorkild I A A1 - Province, Michael A A1 - Parnell, Laurence D A1 - Garcia, Melissa E A1 - Bandinelli, Stefania A1 - Orho-Melander, Marju A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Pennell, Craig E A1 - Kiefte-de Jong, Jessica C A1 - Kähönen, Mika A1 - Young, Kristin L A1 - Pedersen, Oluf A1 - Aslibekyan, Stella A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Zillikens, M Carola A1 - Raitakari, Olli T A1 - North, Kari E A1 - Overvad, Kim A1 - Arnett, Donna K A1 - Hofman, Albert A1 - Lehtimäki, Terho A1 - Tjønneland, Anne A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Franco, Oscar H A1 - German, J Bruce A1 - Siscovick, David S A1 - Cupples, L Adrienne A1 - Ordovas, Jose M AB -

SCOPE: 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.

ER - TY - JOUR T1 - Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. JF - Nat Commun Y1 - 2017 A1 - Joshi, Peter K A1 - Pirastu, Nicola A1 - Kentistou, Katherine A A1 - Fischer, Krista A1 - Hofer, Edith A1 - Schraut, Katharina E A1 - Clark, David W A1 - Nutile, Teresa A1 - Barnes, Catriona L K A1 - Timmers, Paul R H J A1 - Shen, Xia A1 - Gandin, Ilaria A1 - McDaid, Aaron F A1 - Hansen, Thomas Folkmann A1 - Gordon, Scott D A1 - Giulianini, Franco A1 - Boutin, Thibaud S A1 - Abdellaoui, Abdel A1 - Zhao, Wei A1 - Medina-Gómez, Carolina A1 - Bartz, Traci M A1 - Trompet, Stella A1 - Lange, Leslie A A1 - Raffield, Laura A1 - van der Spek, Ashley A1 - Galesloot, Tessel E A1 - Proitsi, Petroula A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Payton, Antony A1 - Murgia, Federico A1 - Concas, Maria Pina A1 - Biino, Ginevra A1 - Tajuddin, Salman M A1 - Seppälä, Ilkka A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Børglum, Anders D A1 - Campbell, Archie A1 - Demerath, Ellen W A1 - Demuth, Ilja A1 - Faul, Jessica D A1 - Ford, Ian A1 - Gialluisi, Alessandro A1 - Gögele, Martin A1 - Graff, Mariaelisa A1 - Hingorani, Aroon A1 - Hottenga, Jouke-Jan A1 - Hougaard, David M A1 - Hurme, Mikko A A1 - Ikram, M Arfan A1 - Jylhä, Marja A1 - Kuh, Diana A1 - Ligthart, Lannie A1 - Lill, Christina M A1 - Lindenberger, Ulman A1 - Lumley, Thomas A1 - Mägi, Reedik A1 - Marques-Vidal, Pedro A1 - Medland, Sarah E A1 - Milani, Lili A1 - Nagy, Reka A1 - Ollier, William E R A1 - Peyser, Patricia A A1 - Pramstaller, Peter P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Steinhagen-Thiessen, Elisabeth A1 - van Rooij, Frank J A A1 - Verbeek, André L A1 - Vermeulen, Sita H A1 - Vollenweider, Peter A1 - Wang, Yunpeng A1 - Werge, Thomas A1 - Whitfield, John B A1 - Zonderman, Alan B A1 - Lehtimäki, Terho A1 - Evans, Michele K A1 - Pirastu, Mario A1 - Fuchsberger, Christian A1 - Bertram, Lars A1 - Pendleton, Neil A1 - Kardia, Sharon L R A1 - Ciullo, Marina A1 - Becker, Diane M A1 - Wong, Andrew A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - Jukema, J Wouter A1 - Kiemeney, Lambertus A1 - Uitterlinden, André G A1 - Franceschini, Nora A1 - North, Kari E A1 - Weir, David R A1 - Metspalu, Andres A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Chasman, Daniel A1 - Martin, Nicholas G A1 - Sattar, Naveed A1 - Campbell, Harry A1 - Esko, Tõnu A1 - Kutalik, Zoltán A1 - Wilson, James F AB -

Genomic 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.

VL - 8 IS - 1 ER - TY - JOUR T1 - {Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits JF - Nat Commun Y1 - 2017 A1 - Justice, A. E. A1 - Winkler, T. W. A1 - Feitosa, M. F. A1 - Graff, M. A1 - Fisher, V. A. A1 - Young, K. A1 - Barata, L. A1 - Deng, X. A1 - Czajkowski, J. A1 - Hadley, D. A1 - Ngwa, J. S. A1 - Ahluwalia, T. S. A1 - Chu, A. Y. A1 - Heard-Costa, N. L. A1 - Lim, E. A1 - Perez, J. A1 - Eicher, J. D. A1 - Kutalik, Z. A1 - Xue, L. A1 - Mahajan, A. A1 - Renstr?m, F. A1 - Wu, J. A1 - Qi, Q. A1 - Ahmad, S. A1 - Alfred, T. A1 - Amin, N. A1 - Bielak, L. F. A1 - Bonnefond, A. A1 - Bragg, J. A1 - Cadby, G. A1 - Chittani, M. A1 - Coggeshall, S. A1 - Corre, T. A1 - Direk, N. A1 - Eriksson, J. A1 - Fischer, K. A1 - Gorski, M. A1 - Neergaard Harder, M. A1 - Horikoshi, M. A1 - Huang, T. A1 - Huffman, J. E. A1 - Jackson, A. U. A1 - Justesen, J. M. A1 - Kanoni, S. A1 - Kinnunen, L. A1 - Kleber, M. E. A1 - Komulainen, P. A1 - Kumari, M. A1 - Lim, U. A1 - Luan, J. A1 - Lyytik?inen, L. P. A1 - Mangino, M. A1 - Manichaikul, A. A1 - Marten, J. A1 - Middelberg, R. P. S. A1 - M?ller-Nurasyid, M. A1 - Navarro, P. A1 - P?russe, L. A1 - Pervjakova, N. A1 - Sarti, C. A1 - Smith, A. V. A1 - Smith, J. A. A1 - Stan??kov?, A. A1 - Strawbridge, R. J. A1 - Stringham, H. M. A1 - Sung, Y. J. A1 - Tanaka, T. A1 - Teumer, A. A1 - Trompet, S. A1 - van der Laan, S. W. A1 - van der Most, P. J. A1 - Van Vliet-Ostaptchouk, J. V. A1 - Vedantam, S. L. A1 - Verweij, N. A1 - Vink, J. M. A1 - Vitart, V. A1 - Wu, Y. A1 - Yengo, L. A1 - Zhang, W. A1 - Hua Zhao, J. A1 - Zimmermann, M. E. A1 - Zubair, N. A1 - Abecasis, G. R. A1 - Adair, L. S. A1 - Afaq, S. A1 - Afzal, U. A1 - Bakker, S. J. L. A1 - Bartz, T. M. A1 - Beilby, J. A1 - Bergman, R. N. A1 - Bergmann, S. A1 - Biffar, R. A1 - Blangero, J. A1 - Boerwinkle, E. A1 - Bonnycastle, L. L. A1 - Bottinger, E. A1 - Braga, D. A1 - Buckley, B. M. A1 - Buyske, S. A1 - Campbell, H. A1 - Chambers, J. C. A1 - Collins, F. S. A1 - Curran, J. E. A1 - de Borst, G. J. A1 - de Craen, A. J. M. A1 - de Geus, E. J. C. A1 - Dedoussis, G. A1 - Delgado, G. E. A1 - den Ruijter, H. M. A1 - Eiriksdottir, G. A1 - Eriksson, A. L. A1 - Esko, T. A1 - Faul, J. D. A1 - Ford, I. A1 - Forrester, T. A1 - Gertow, K. A1 - Gigante, B. A1 - Glorioso, N. A1 - Gong, J. A1 - Grallert, H. A1 - Grammer, T. B. A1 - Grarup, N. A1 - Haitjema, S. A1 - Hallmans, G. A1 - Hamsten, A. A1 - Hansen, T. A1 - Harris, T. B. A1 - Hartman, C. A. A1 - Hassinen, M. A1 - Hastie, N. D. A1 - Heath, A. C. A1 - Hernandez, D. A1 - Hindorff, L. A1 - Hocking, L. J. A1 - Hollensted, M. A1 - Holmen, O. L. A1 - Homuth, G. A1 - Jan Hottenga, J. A1 - Huang, J. A1 - Hung, J. A1 - Hutri-K?h?nen, N. A1 - Ingelsson, E. A1 - James, A. L. A1 - Jansson, J. O. A1 - Jarvelin, M. R. A1 - Jhun, M. A. A1 - J?rgensen, M. E. A1 - Juonala, M. A1 - K?h?nen, M. A1 - Karlsson, M. A1 - Koistinen, H. A. A1 - Kolcic, I. A1 - Kolovou, G. A1 - Kooperberg, C. A1 - Kr?mer, B. K. A1 - Kuusisto, J. A1 - Kval?y, K. A1 - Lakka, T. A. A1 - Langenberg, C. A1 - Launer, L. J. A1 - Leander, K. A1 - Lee, N. R. A1 - Lind, L. A1 - Lindgren, C. M. A1 - Linneberg, A. A1 - Lobbens, S. A1 - Loh, M. A1 - Lorentzon, M. A1 - Luben, R. A1 - Lubke, G. A1 - Ludolph-Donislawski, A. A1 - Lupoli, S. A1 - Madden, P. A. F. A1 - M?nnikk?, R. A1 - Marques-Vidal, P. A1 - Martin, N. G. A1 - McKenzie, C. A. A1 - McKnight, B. A1 - Mellstr?m, D. A1 - Menni, C. A1 - Montgomery, G. W. A1 - Musk, A. B. A1 - Narisu, N. A1 - Nauck, M. A1 - Nolte, I. M. A1 - Oldehinkel, A. J. A1 - Olden, M. A1 - Ong, K. K. A1 - Padmanabhan, S. A1 - Peyser, P. A. A1 - Pisinger, C. A1 - Porteous, D. J. A1 - Raitakari, O. T. A1 - Rankinen, T. A1 - Rao, D. C. A1 - Rasmussen-Torvik, L. J. A1 - Rawal, R. A1 - Rice, T. A1 - Ridker, P. M. A1 - Rose, L. M. A1 - Bien, S. A. A1 - Rudan, I. A1 - Sanna, S. A1 - Sarzynski, M. A. A1 - Sattar, N. A1 - Savonen, K. A1 - Schlessinger, D. A1 - Scholtens, S. A1 - Schurmann, C. A1 - Scott, R. A. A1 - Sennblad, B. A1 - Siemelink, M. A. A1 - Silbernagel, G. A1 - Slagboom, P. E. A1 - Snieder, H. A1 - Staessen, J. A. A1 - Stott, D. J. A1 - Swertz, M. A. A1 - Swift, A. J. A1 - Taylor, K. D. A1 - Tayo, B. O. A1 - Thorand, B. A1 - Thuillier, D. A1 - Tuomilehto, J. A1 - Uitterlinden, A. G. A1 - Vandenput, L. A1 - Vohl, M. C. A1 - V?lzke, H. A1 - Vonk, J. M. A1 - Waeber, G. A1 - Waldenberger, M. A1 - Westendorp, R. G. J. A1 - Wild, S. A1 - Willemsen, G. A1 - Wolffenbuttel, B. H. R. A1 - Wong, A. A1 - Wright, A. F. A1 - Zhao, W. A1 - Zillikens, M. C. A1 - Baldassarre, D. A1 - Balkau, B. A1 - Bandinelli, S. A1 - B?ger, C. A. A1 - Boomsma, D. I. A1 - Bouchard, C. A1 - Bruinenberg, M. A1 - Chasman, D. I. A1 - Chen, Y. D. A1 - Chines, P. S. A1 - Cooper, R. S. A1 - Cucca, F. A1 - Cusi, D. A1 - Faire, U. A1 - Ferrucci, L. A1 - Franks, P. W. A1 - Froguel, P. A1 - Gordon-Larsen, P. A1 - Grabe, H. J. A1 - Gudnason, V. A1 - Haiman, C. A. A1 - Hayward, C. A1 - Hveem, K. A1 - Johnson, A. D. A1 - Wouter Jukema, J. A1 - Kardia, S. L. R. A1 - Kivimaki, M. A1 - Kooner, J. S. A1 - Kuh, D. A1 - Laakso, M. A1 - Lehtim?ki, T. A1 - Marchand, L. L. A1 - M?rz, W. A1 - McCarthy, M. I. A1 - Metspalu, A. A1 - Morris, A. P. A1 - Ohlsson, C. A1 - Palmer, L. J. A1 - Pasterkamp, G. A1 - Pedersen, O. A1 - Peters, A. A1 - Peters, U. A1 - Polasek, O. A1 - Psaty, B. M. A1 - Qi, L. A1 - Rauramaa, R. A1 - Smith, B. H. A1 - S?rensen, T. I. A. A1 - Strauch, K. A1 - Tiemeier, H. A1 - Tremoli, E. A1 - van der Harst, P. A1 - Vestergaard, H. A1 - Vollenweider, P. A1 - Wareham, N. J. A1 - Weir, D. R. A1 - Whitfield, J. B. A1 - Wilson, J. F. A1 - Tyrrell, J. A1 - Frayling, T. M. A1 - Barroso, I. A1 - Boehnke, M. A1 - Deloukas, P. A1 - Fox, C. S. A1 - Hirschhorn, J. N. A1 - Hunter, D. J. A1 - Spector, T. D. A1 - Strachan, D. P. A1 - van Duijn, C. M. A1 - Heid, I. M. A1 - Mohlke, K. L. A1 - Marchini, J. A1 - Loos, R. J. F. A1 - Kilpel?inen, T. O. A1 - Liu, C. T. A1 - Borecki, I. B. A1 - North, K. E. A1 - Cupples, L. A. AB - Few 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. VL - 8 ER - TY - JOUR T1 - Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. JF - Am J Hum Genet Y1 - 2017 A1 - van Rooij, Frank J A A1 - Qayyum, Rehan A1 - Smith, Albert V A1 - Zhou, Yi A1 - Trompet, Stella A1 - Tanaka, Toshiko A1 - Keller, Margaux F A1 - Chang, Li-Ching A1 - Schmidt, Helena A1 - Yang, Min-Lee A1 - Chen, Ming-Huei A1 - Hayes, James A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Mueller, Christian A1 - Lange, Leslie A1 - Floyd, James S A1 - Ghanbari, Mohsen A1 - Zonderman, Alan B A1 - Jukema, J Wouter A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Desch, Karl C A1 - Saba, Yasaman A1 - Ozel, Ayse B A1 - Snively, Beverly M A1 - Wu, Jer-Yuarn A1 - Schmidt, Reinhold A1 - Fornage, Myriam A1 - Klein, Robert J A1 - Fox, Caroline S A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Wild, Philipp S A1 - Stott, David J A1 - Ford, Ian A1 - Slagboom, P Eline A1 - Yang, Jaden A1 - Chu, Audrey Y A1 - Lambert, Amy J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofer, Edith A1 - Ginsburg, David A1 - Hu, Bella A1 - Keating, Brendan A1 - Schick, Ursula M A1 - Brody, Jennifer A A1 - Li, Jun Z A1 - Chen, Zhao A1 - Zeller, Tanja A1 - Guralnik, Jack M A1 - Chasman, Daniel I A1 - Peters, Luanne L A1 - Kubo, Michiaki A1 - Becker, Diane M A1 - Li, Jin A1 - Eiriksdottir, Gudny A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Grossmann, Vera A1 - Patel, Kushang V A1 - Chen, Chien-Hsiun A1 - Ridker, Paul M A1 - Tang, Hua A1 - Launer, Lenore J A1 - Rice, Kenneth M A1 - Li-Gao, Ruifang A1 - Ferrucci, Luigi A1 - Evans, Michelle K A1 - Choudhuri, Avik A1 - Trompouki, Eirini A1 - Abraham, Brian J A1 - Yang, Song A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Kooperberg, Charles A1 - Harris, Tamara B A1 - Jee, Sun Ha A1 - Coresh, Josef A1 - Tsai, Fuu-Jen A1 - Longo, Dan L A1 - Chen, Yuan-Tsong A1 - Felix, Janine F A1 - Yang, Qiong A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Becker, Lewis C A1 - Mook-Kanamori, Dennis O A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J A1 - Dehghan, Abbas A1 - Cupples, L Adrienne A1 - Nalls, Michael A A1 - Morris, Andrew P A1 - Okada, Yukinori A1 - Reiner, Alexander P A1 - Zon, Leonard I A1 - Ganesh, Santhi K AB -

Genome-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.

VL - 100 IS - 1 ER - TY - JOUR T1 - Health and Functional Status of Adults Aged 90 Years in the United States. JF - JAMA Intern Med Y1 - 2017 A1 - Odden, Michelle C A1 - Koh, William Jen Hoe A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Newman, Anne B VL - 177 IS - 5 ER - TY - JOUR T1 - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. JF - PLoS Med Y1 - 2017 A1 - Wheeler, Eleanor A1 - Leong, Aaron A1 - Liu, Ching-Ti A1 - Hivert, Marie-France A1 - Strawbridge, Rona J A1 - Podmore, Clara A1 - Li, Man A1 - Yao, Jie A1 - Sim, Xueling A1 - Hong, Jaeyoung A1 - Chu, Audrey Y A1 - Zhang, Weihua A1 - Wang, Xu A1 - Chen, Peng A1 - Maruthur, Nisa M A1 - Porneala, Bianca C A1 - Sharp, Stephen J A1 - Jia, Yucheng A1 - Kabagambe, Edmond K A1 - Chang, Li-Ching A1 - Chen, Wei-Min A1 - Elks, Cathy E A1 - Evans, Daniel S A1 - Fan, Qiao A1 - Giulianini, Franco A1 - Go, Min Jin A1 - Hottenga, Jouke-Jan A1 - Hu, Yao A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kim, Young Jin A1 - Kleber, Marcus E A1 - Ladenvall, Claes A1 - Lecoeur, Cécile A1 - Lim, Sing-Hui A1 - Lu, Yingchang A1 - Mahajan, Anubha A1 - Marzi, Carola A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nolte, Ilja M A1 - Rose, Lynda M A1 - Rybin, Denis V A1 - Sanna, Serena A1 - Shi, Yuan A1 - Stram, Daniel O A1 - Takeuchi, Fumihiko A1 - Tan, Shu Pei A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Wong, Andrew A1 - Yengo, Loic A1 - Zhao, Wanting A1 - Goel, Anuj A1 - Martinez Larrad, Maria Teresa A1 - Radke, Dörte A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - van Iperen, Erik P A A1 - Abecasis, Goncalo A1 - Afaq, Saima A1 - Alizadeh, Behrooz Z A1 - Bertoni, Alain G A1 - Bonnefond, Amélie A1 - Böttcher, Yvonne A1 - Bottinger, Erwin P A1 - Campbell, Harry A1 - Carlson, Olga D A1 - Chen, Chien-Hsiun A1 - Cho, Yoon Shin A1 - Garvey, W Timothy A1 - Gieger, Christian A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Hamsten, Anders A1 - Hartman, Catharina A A1 - Herder, Christian A1 - Hsiung, Chao Agnes A1 - Huang, Jie A1 - Igase, Michiya A1 - Isono, Masato A1 - Katsuya, Tomohiro A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kohara, Katsuhiko A1 - Kovacs, Peter A1 - Lee, Juyoung A1 - Lee, Wen-Jane A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Liu, Jianjun A1 - Lobbens, Stephane A1 - Luan, Jian'an A1 - Lyssenko, Valeriya A1 - Meitinger, Thomas A1 - Miki, Tetsuro A1 - Miljkovic, Iva A1 - Moon, Sanghoon A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Pankow, James S A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Ramos, Paula S A1 - Rasmussen-Torvik, Laura A1 - Rathmann, Wolfgang A1 - Rich, Stephen S A1 - Robertson, Neil R A1 - Roden, Michael A1 - Roussel, Ronan A1 - Rudan, Igor A1 - Scott, Robert A A1 - Scott, William R A1 - Sennblad, Bengt A1 - Siscovick, David S A1 - Strauch, Konstantin A1 - Sun, Liang A1 - Swertz, Morris A1 - Tajuddin, Salman M A1 - Taylor, Kent D A1 - Teo, Yik-Ying A1 - Tham, Yih Chung A1 - Tönjes, Anke A1 - Wareham, Nicholas J A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Hingorani, Aroon D A1 - Egan, Josephine A1 - Ferrucci, Luigi A1 - Hovingh, G Kees A1 - Jula, Antti A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Njølstad, Inger A1 - Palmer, Colin N A A1 - Serrano Ríos, Manuel A1 - Stumvoll, Michael A1 - Watkins, Hugh A1 - Aung, Tin A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boomsma, Dorret I A1 - Bornstein, Stefan R A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chen, Yduan-Tsong A1 - Cheng, Ching-Yu A1 - Cucca, Francesco A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Evans, Michele K A1 - Fornage, Myriam A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Groop, Leif A1 - Gross, Myron D A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heng, Chew-Kiat A1 - Ingelsson, Erik A1 - Kato, Norihiro A1 - Kim, Bong-Jo A1 - Koh, Woon-Puay A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lin, Xu A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - März, Winfried A1 - McCarthy, Mark I A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pedersen, Nancy L A1 - Pereira, Mark A A1 - Peters, Annette A1 - Ridker, Paul M A1 - Sabanayagam, Charumathi A1 - Sale, Michele A1 - Saleheen, Danish A1 - Saltevo, Juha A1 - Schwarz, Peter Eh A1 - Sheu, Wayne H H A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Tabara, Yasuharu A1 - Tuomilehto, Jaakko A1 - van Dam, Rob M A1 - Wilson, James G A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Soranzo, Nicole A1 - Guo, Xiuqing A1 - Roberts, David J A1 - Florez, Jose C A1 - Sladek, Robert A1 - Dupuis, Josée A1 - Morris, Andrew P A1 - Tai, E-Shyong A1 - Selvin, Elizabeth A1 - Rotter, Jerome I A1 - Langenberg, Claudia A1 - Barroso, Inês A1 - Meigs, James B KW - Diabetes Mellitus, Type 2 KW - Genetic Variation KW - Genome-Wide Association Study KW - Glycated Hemoglobin A KW - Humans KW - Phenotype KW - Risk AB -

BACKGROUND: 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.

VL - 14 IS - 9 ER - TY - JOUR T1 - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JF - Nat Commun Y1 - 2017 A1 - Zillikens, M Carola A1 - Demissie, Serkalem A1 - Hsu, Yi-Hsiang A1 - Yerges-Armstrong, Laura M A1 - Chou, Wen-Chi A1 - Stolk, Lisette A1 - Livshits, Gregory A1 - Broer, Linda A1 - Johnson, Toby A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Malkin, Ida A1 - Ried, Janina S A1 - Smith, Albert V A1 - Thorleifsson, Gudmar A1 - Vandenput, Liesbeth A1 - Hua Zhao, Jing A1 - Zhang, Weihua A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Baier, Leslie J A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Biffar, Rainer A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos Obanda, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Cederberg, Henna A1 - Chen, Zhao A1 - Cho, Nam H A1 - Jin Choi, Hyung A1 - Claussnitzer, Melina A1 - Collins, Francis A1 - Cummings, Steven R A1 - De Jager, Philip L A1 - Demuth, Ilja A1 - Dhonukshe-Rutten, Rosalie A M A1 - Diatchenko, Luda A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Erdos, Mike A1 - Eriksson, Johan G A1 - Eriksson, Joel A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Girke, Thomas A1 - Glazer, Nicole L A1 - Grallert, Harald A1 - Grewal, Jagvir A1 - Han, Bok-Ghee A1 - Hanson, Robert L A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Hoffman, Eric P A1 - Homuth, Georg A1 - Hsueh, Wen-Chi A1 - Hubal, Monica J A1 - Hubbard, Alan A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koistinen, Heikki A A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Launer, Lenore J A1 - Lee, Jong-Young A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Liu, Tian A1 - Liu, Youfang A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Maixner, William A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Melov, Simon A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Newman, Anne A1 - Nielson, Carrie M A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Parker, Stephen C J A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Prince, Richard L A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schadt, Eric E A1 - Schipf, Sabine A1 - Scott, Laura A1 - Sehmi, Joban A1 - Shen, Jian A1 - Soo Shin, Chan A1 - Sigurdsson, Gunnar A1 - Smith, Shad A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Steinhagen-Thiessen, Elisabeth A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Tan, Sian-Tsung A1 - Tarnopolsky, Mark A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Tuomilehto, Jaakko A1 - van Schoor, Natasja M A1 - Verma, Arjun A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - Weedon, Michael N A1 - Welch, Ryan A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Xie, Weijia A1 - Yu, Lei A1 - Zhou, Yanhua A1 - Chambers, John C A1 - Döring, Angela A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Gudnason, Vilmundur A1 - Kooner, Jaspal S A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Ossowski, Vicky A1 - Waterworth, Dawn A1 - Loos, Ruth J F A1 - Karasik, David A1 - Harris, Tamara B A1 - Ohlsson, Claes A1 - Kiel, Douglas P AB -

Lean 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.

VL - 8 IS - 1 ER - TY - JOUR T1 - Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. JF - Nat Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Rienstra, Michiel A1 - Roselli, Carolina A1 - Yin, Xiaoyan A1 - Geelhoed, Bastiaan A1 - Barnard, John A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Smith, Albert V A1 - Albert, Christine M A1 - Chaffin, Mark A1 - Tucker, Nathan R A1 - Li, Molong A1 - Klarin, Derek A1 - Bihlmeyer, Nathan A A1 - Low, Siew-Kee A1 - Weeke, Peter E A1 - Müller-Nurasyid, Martina A1 - Smith, J Gustav A1 - Brody, Jennifer A A1 - Niemeijer, Maartje N A1 - Dörr, Marcus A1 - Trompet, Stella A1 - Huffman, Jennifer A1 - Gustafsson, Stefan A1 - Schurmann, Claudia A1 - Kleber, Marcus E A1 - Lyytikäinen, Leo-Pekka A1 - Seppälä, Ilkka A1 - Malik, Rainer A1 - Horimoto, Andrea R V R A1 - Perez, Marco A1 - Sinisalo, Juha A1 - Aeschbacher, Stefanie A1 - Thériault, Sébastien A1 - Yao, Jie A1 - Radmanesh, Farid A1 - Weiss, Stefan A1 - Teumer, Alexander A1 - Choi, Seung Hoan A1 - Weng, Lu-Chen A1 - Clauss, Sebastian A1 - Deo, Rajat A1 - Rader, Daniel J A1 - Shah, Svati H A1 - Sun, Albert A1 - Hopewell, Jemma C A1 - Debette, Stephanie A1 - Chauhan, Ganesh A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Paré, Guillaume A1 - Kamatani, Yoichiro A1 - Hagemeijer, Yanick P A1 - Verweij, Niek A1 - Siland, Joylene E A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Bis, Joshua C A1 - Perz, Siegfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Magnani, Jared W A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shoemaker, M Benjamin A1 - Padmanabhan, Sandosh A1 - Haessler, Jeffrey A1 - Bartz, Traci M A1 - Waldenberger, Melanie A1 - Lichtner, Peter A1 - Arendt, Marina A1 - Krieger, Jose E A1 - Kähönen, Mika A1 - Risch, Lorenz A1 - Mansur, Alfredo J A1 - Peters, Annette A1 - Smith, Blair H A1 - Lind, Lars A1 - Scott, Stuart A A1 - Lu, Yingchang A1 - Bottinger, Erwin B A1 - Hernesniemi, Jussi A1 - Lindgren, Cecilia M A1 - Wong, Jorge A A1 - Huang, Jie A1 - Eskola, Markku A1 - Morris, Andrew P A1 - Ford, Ian A1 - Reiner, Alex P A1 - Delgado, Graciela A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Sandhu, Roopinder K A1 - Li, Man A1 - Boerwinkle, Eric A1 - Eisele, Lewin A1 - Lannfelt, Lars A1 - Rost, Natalia A1 - Anderson, Christopher D A1 - Taylor, Kent D A1 - Campbell, Archie A1 - Magnusson, Patrik K A1 - Porteous, David A1 - Hocking, Lynne J A1 - Vlachopoulou, Efthymia A1 - Pedersen, Nancy L A1 - Nikus, Kjell A1 - Orho-Melander, Marju A1 - Hamsten, Anders A1 - Heeringa, Jan A1 - Denny, Joshua C A1 - Kriebel, Jennifer A1 - Darbar, Dawood A1 - Newton-Cheh, Christopher A1 - Shaffer, Christian A1 - Macfarlane, Peter W A1 - Heilmann-Heimbach, Stefanie A1 - Almgren, Peter A1 - Huang, Paul L A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Völker, Uwe A1 - Jöckel, Karl-Heinz A1 - Sinner, Moritz F A1 - Lin, Henry J A1 - Guo, Xiuqing A1 - Dichgans, Martin A1 - Ingelsson, Erik A1 - Kooperberg, Charles A1 - Melander, Olle A1 - Loos, Ruth J F A1 - Laurikka, Jari A1 - Conen, David A1 - Rosand, Jonathan A1 - van der Harst, Pim A1 - Lokki, Marja-Liisa A1 - Kathiresan, Sekar A1 - Pereira, Alexandre A1 - Jukema, J Wouter A1 - Hayward, Caroline A1 - Rotter, Jerome I A1 - März, Winfried A1 - Lehtimäki, Terho A1 - Stricker, Bruno H A1 - Chung, Mina K A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Roden, Dan M A1 - Kääb, Stefan A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Tanaka, Toshihiro A1 - Lunetta, Kathryn L A1 - Lubitz, Steven A A1 - Ellinor, Patrick T AB -

Atrial 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.

VL - 49 IS - 6 ER - TY - JOUR T1 - Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. JF - Cell Rep Y1 - 2017 A1 - Lam, Max A1 - Trampush, Joey W A1 - Yu, Jin A1 - Knowles, Emma A1 - Davies, Gail A1 - Liewald, David C A1 - Starr, John M A1 - Djurovic, Srdjan A1 - Melle, Ingrid A1 - Sundet, Kjetil A1 - Christoforou, Andrea A1 - Reinvang, Ivar A1 - DeRosse, Pamela A1 - Lundervold, Astri J A1 - Steen, Vidar M A1 - Espeseth, Thomas A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Eriksson, Johan G A1 - Giegling, Ina A1 - Konte, Bettina A1 - Roussos, Panos A1 - Giakoumaki, Stella A1 - Burdick, Katherine E A1 - Payton, Antony A1 - Ollier, William A1 - Chiba-Falek, Ornit A1 - Attix, Deborah K A1 - Need, Anna C A1 - Cirulli, Elizabeth T A1 - Voineskos, Aristotle N A1 - Stefanis, Nikos C A1 - Avramopoulos, Dimitrios A1 - Hatzimanolis, Alex A1 - Arking, Dan E A1 - Smyrnis, Nikolaos A1 - Bilder, Robert M A1 - Freimer, Nelson A A1 - Cannon, Tyrone D A1 - London, Edythe A1 - Poldrack, Russell A A1 - Sabb, Fred W A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Scult, Matthew A A1 - Dickinson, Dwight A1 - Straub, Richard E A1 - Donohoe, Gary A1 - Morris, Derek A1 - Corvin, Aiden A1 - Gill, Michael A1 - Hariri, Ahmad R A1 - Weinberger, Daniel R A1 - Pendleton, Neil A1 - Bitsios, Panos A1 - Rujescu, Dan A1 - Lahti, Jari A1 - Le Hellard, Stephanie A1 - Keller, Matthew C A1 - Andreassen, Ole A A1 - Deary, Ian J A1 - Glahn, David C A1 - Malhotra, Anil K A1 - Lencz, Todd AB -

Here, 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.

VL - 21 IS - 9 ER - TY - JOUR T1 - Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. JF - J Clin Invest Y1 - 2017 A1 - Wild, Philipp S A1 - Felix, Janine F A1 - Schillert, Arne A1 - Teumer, Alexander A1 - Chen, Ming-Huei A1 - Leening, Maarten J G A1 - Völker, Uwe A1 - Großmann, Vera A1 - Brody, Jennifer A A1 - Irvin, Marguerite R A1 - Shah, Sanjiv J A1 - Pramana, Setia A1 - Lieb, Wolfgang A1 - Schmidt, Reinhold A1 - Stanton, Alice V A1 - Malzahn, Dörthe A1 - Smith, Albert Vernon A1 - Sundström, Johan A1 - Minelli, Cosetta A1 - Ruggiero, Daniela A1 - Lyytikäinen, Leo-Pekka A1 - Tiller, Daniel A1 - Smith, J Gustav A1 - Monnereau, Claire A1 - Di Tullio, Marco R A1 - Musani, Solomon K A1 - Morrison, Alanna C A1 - Pers, Tune H A1 - Morley, Michael A1 - Kleber, Marcus E A1 - Aragam, Jayashri A1 - Benjamin, Emelia J A1 - Bis, Joshua C A1 - Bisping, Egbert A1 - Broeckel, Ulrich A1 - Cheng, Susan A1 - Deckers, Jaap W A1 - del Greco M, Fabiola A1 - Edelmann, Frank A1 - Fornage, Myriam A1 - Franke, Lude A1 - Friedrich, Nele A1 - Harris, Tamara B A1 - Hofer, Edith A1 - Hofman, Albert A1 - Huang, Jie A1 - Hughes, Alun D A1 - Kähönen, Mika A1 - Investigators, Knhi A1 - Kruppa, Jochen A1 - Lackner, Karl J A1 - Lannfelt, Lars A1 - Laskowski, Rafael A1 - Launer, Lenore J A1 - Leosdottir, Margrét A1 - Lin, Honghuang A1 - Lindgren, Cecilia M A1 - Loley, Christina A1 - MacRae, Calum A A1 - Mascalzoni, Deborah A1 - Mayet, Jamil A1 - Medenwald, Daniel A1 - Morris, Andrew P A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nappo, Stefania A1 - Nilsson, Peter M A1 - Nuding, Sebastian A1 - Nutile, Teresa A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pietzner, Diana A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Ruohonen, Saku T A1 - Sacco, Ralph L A1 - Samdarshi, Tandaw E A1 - Schmidt, Helena A1 - Sharp, Andrew S P A1 - Shields, Denis C A1 - Sorice, Rossella A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Surendran, Praveen A1 - Thom, Simon A1 - Töglhofer, Anna M A1 - Uitterlinden, André G A1 - Wachter, Rolf A1 - Völzke, Henry A1 - Ziegler, Andreas A1 - Münzel, Thomas A1 - März, Winfried A1 - Cappola, Thomas P A1 - Hirschhorn, Joel N A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Fox, Ervin R A1 - Dueker, Nicole D A1 - Jaddoe, Vincent W V A1 - Melander, Olle A1 - Russ, Martin A1 - Lehtimäki, Terho A1 - Ciullo, Marina A1 - Hicks, Andrew A A1 - Lind, Lars A1 - Gudnason, Vilmundur A1 - Pieske, Burkert A1 - Barron, Anthony J A1 - Zweiker, Robert A1 - Schunkert, Heribert A1 - Ingelsson, Erik A1 - Liu, Kiang A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Blankenberg, Stefan A1 - Larson, Martin G A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Zeller, Tanja A1 - Vasan, Ramachandran S A1 - Dörr, Marcus AB -

BACKGROUND: 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.

VL - 127 IS - 5 ER - TY - JOUR T1 - Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. JF - Nat Commun Y1 - 2017 A1 - Willems, Sara M A1 - Wright, Daniel J A1 - Day, Felix R A1 - Trajanoska, Katerina A1 - Joshi, Peter K A1 - Morris, John A A1 - Matteini, Amy M A1 - Garton, Fleur C A1 - Grarup, Niels A1 - Oskolkov, Nikolay A1 - Thalamuthu, Anbupalam A1 - Mangino, Massimo A1 - Liu, Jun A1 - Demirkan, Ayse A1 - Lek, Monkol A1 - Xu, Liwen A1 - Wang, Guan A1 - Oldmeadow, Christopher A1 - Gaulton, Kyle J A1 - Lotta, Luca A A1 - Miyamoto-Mikami, Eri A1 - Rivas, Manuel A A1 - White, Tom A1 - Loh, Po-Ru A1 - Aadahl, Mette A1 - Amin, Najaf A1 - Attia, John R A1 - Austin, Krista A1 - Benyamin, Beben A1 - Brage, Søren A1 - Cheng, Yu-Ching A1 - Cięszczyk, Paweł A1 - Derave, Wim A1 - Eriksson, Karl-Fredrik A1 - Eynon, Nir A1 - Linneberg, Allan A1 - Lucia, Alejandro A1 - Massidda, Myosotis A1 - Mitchell, Braxton D A1 - Miyachi, Motohiko A1 - Murakami, Haruka A1 - Padmanabhan, Sandosh A1 - Pandey, Ashutosh A1 - Papadimitriou, Ioannis A1 - Rajpal, Deepak K A1 - Sale, Craig A1 - Schnurr, Theresia M A1 - Sessa, Francesco A1 - Shrine, Nick A1 - Tobin, Martin D A1 - Varley, Ian A1 - Wain, Louise V A1 - Wray, Naomi R A1 - Lindgren, Cecilia M A1 - MacArthur, Daniel G A1 - Waterworth, Dawn M A1 - McCarthy, Mark I A1 - Pedersen, Oluf A1 - Khaw, Kay-Tee A1 - Kiel, Douglas P A1 - Pitsiladis, Yannis A1 - Fuku, Noriyuki A1 - Franks, Paul W A1 - North, Kathryn N A1 - van Duijn, Cornelia M A1 - Mather, Karen A A1 - Hansen, Torben A1 - Hansson, Ola A1 - Spector, Tim A1 - Murabito, Joanne M A1 - Richards, J Brent A1 - Rivadeneira, Fernando A1 - Langenberg, Claudia A1 - Perry, John R B A1 - Wareham, Nick J A1 - Scott, Robert A AB -

Hand 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.

VL - 8 ER - TY - JOUR T1 - Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. JF - Am J Hum Genet Y1 - 2017 A1 - Manousaki, Despoina A1 - Dudding, Tom A1 - Haworth, Simon A1 - Hsu, Yi-Hsiang A1 - Liu, Ching-Ti A1 - Medina-Gómez, Carolina A1 - Voortman, Trudy A1 - van der Velde, Nathalie A1 - Melhus, Håkan A1 - Robinson-Cohen, Cassianne A1 - Cousminer, Diana L A1 - Nethander, Maria A1 - Vandenput, Liesbeth A1 - Noordam, Raymond A1 - Forgetta, Vincenzo A1 - Greenwood, Celia M T A1 - Biggs, Mary L A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Zemel, Babette S A1 - Mitchell, Jonathan A A1 - Taylor, Bruce A1 - Lorentzon, Mattias A1 - Karlsson, Magnus A1 - Jaddoe, Vincent V W A1 - Tiemeier, Henning A1 - Campos-Obando, Natalia A1 - Franco, Oscar H A1 - Utterlinden, Andre G A1 - Broer, Linda A1 - van Schoor, Natasja M A1 - Ham, Annelies C A1 - Ikram, M Arfan A1 - Karasik, David A1 - de Mutsert, Renée A1 - Rosendaal, Frits R A1 - den Heijer, Martin A1 - Wang, Thomas J A1 - Lind, Lars A1 - Orwoll, Eric S A1 - Mook-Kanamori, Dennis O A1 - Michaëlsson, Karl A1 - Kestenbaum, Bryan A1 - Ohlsson, Claes A1 - Mellström, Dan A1 - de Groot, Lisette C P G M A1 - Grant, Struan F A A1 - Kiel, Douglas P A1 - Zillikens, M Carola A1 - Rivadeneira, Fernando A1 - Sawcer, Stephen A1 - Timpson, Nicholas J A1 - Richards, J Brent KW - Cholestanetriol 26-Monooxygenase KW - Cytochrome P450 Family 2 KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Multiple Sclerosis KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Vitamin D KW - Vitamin D Deficiency AB -

Vitamin 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.

VL - 101 IS - 2 ER - TY - JOUR T1 - Multiancestry Study of Gene-Lifestyle Interactions for Cardiovascular Traits in 610 475 Individuals From 124 Cohorts: Design and Rationale. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Rao, D C A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Schwander, Karen A1 - Borecki, Ingrid A1 - Cupples, L Adrienne A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Psaty, Bruce M AB -

BACKGROUND: 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.

VL - 10 IS - 3 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M AB -

BACKGROUND: 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.

VL - 10 IS - 5 ER - TY - JOUR T1 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Jarvelin, Marjo-Riitta A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stephanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated 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.

ER - TY - JOUR T1 - {Novel genetic loci associated with hippocampal volume JF - Nat Commun Y1 - 2017 A1 - Hibar, D. P. A1 - Adams, H. H. H. A1 - Jahanshad, N. A1 - Chauhan, G. A1 - Stein, J. L. A1 - Hofer, E. A1 - Renteria, M. E. A1 - Bis, J. C. A1 - Arias-Vasquez, A. A1 - Ikram, M. K. A1 - Desrivi?res, S. A1 - Vernooij, M. W. A1 - Abramovic, L. A1 - Alhusaini, S. A1 - Amin, N. A1 - Andersson, M. A1 - Arfanakis, K. A1 - Aribisala, B. S. A1 - Armstrong, N. J. A1 - Athanasiu, L. A1 - Axelsson, T. A1 - Beecham, A. H. A1 - Beiser, A. A1 - Bernard, M. A1 - Blanton, S. H. A1 - Bohlken, M. M. A1 - Boks, M. P. A1 - Bralten, J. A1 - Brickman, A. M. A1 - Carmichael, O. A1 - Chakravarty, M. M. A1 - Chen, Q. A1 - Ching, C. R. K. A1 - Chouraki, V. A1 - Cuellar-Partida, G. A1 - Crivello, F. A1 - den Braber, A. A1 - Doan, N. T. A1 - Ehrlich, S. A1 - Giddaluru, S. A1 - Goldman, A. L. A1 - Gottesman, R. F. A1 - Grimm, O. A1 - Griswold, M. E. A1 - Guadalupe, T. A1 - Gutman, B. A. A1 - Hass, J. A1 - Haukvik, U. K. A1 - Hoehn, D. A1 - Holmes, A. J. A1 - Hoogman, M. A1 - Janowitz, D. A1 - Jia, T. A1 - J?rgensen, K. N. A1 - Karbalai, N. A1 - Kasperaviciute, D. A1 - Kim, S. A1 - Klein, M. A1 - Kraemer, B. A1 - Lee, P. H. A1 - Liewald, D. C. M. A1 - Lopez, L. M. A1 - Luciano, M. A1 - Macare, C. A1 - Marquand, A. F. A1 - Matarin, M. A1 - Mather, K. A. A1 - Mattheisen, M. A1 - McKay, D. R. A1 - Milaneschi, Y. A1 - Mu?oz Maniega, S. A1 - Nho, K. A1 - Nugent, A. C. A1 - Nyquist, P. A1 - Loohuis, L. M. O. A1 - Oosterlaan, J. A1 - Papmeyer, M. A1 - Pirpamer, L. A1 - P?tz, B. A1 - Ramasamy, A. A1 - Richards, J. S. A1 - Risacher, S. L. A1 - Roiz-Santia?ez, R. A1 - Rommelse, N. A1 - Ropele, S. A1 - Rose, E. J. A1 - Royle, N. A. A1 - Rundek, T. A1 - S?mann, P. G. A1 - Saremi, A. A1 - Satizabal, C. L. A1 - Schmaal, L. A1 - Schork, A. J. A1 - Shen, L. A1 - Shin, J. A1 - Shumskaya, E. A1 - Smith, A. V. A1 - Sprooten, E. A1 - Strike, L. T. A1 - Teumer, A. A1 - Tordesillas-Gutierrez, D. A1 - Toro, R. A1 - Trabzuni, D. A1 - Trompet, S. A1 - Vaidya, D. A1 - van der Grond, J. A1 - van der Lee, S. J. A1 - van der Meer, D. A1 - van Donkelaar, M. M. J. A1 - Van Eijk, K. R. A1 - van Erp, T. G. M. A1 - van Rooij, D. A1 - Walton, E. A1 - Westlye, L. T. A1 - Whelan, C. D. A1 - Windham, B. G. A1 - Winkler, A. M. A1 - Wittfeld, K. A1 - Woldehawariat, G. A1 - Wolf, C. A1 - Wolfers, T. A1 - Yanek, L. R. A1 - Yang, J. A1 - Zijdenbos, A. A1 - Zwiers, M. P. A1 - Agartz, I. A1 - Almasy, L. A1 - Ames, D. A1 - Amouyel, P. A1 - Andreassen, O. A. A1 - Arepalli, S. A1 - Assareh, A. A. A1 - Barral, S. A1 - Bastin, M. E. A1 - Becker, D. M. A1 - Becker, J. T. A1 - Bennett, D. A. A1 - Blangero, J. A1 - van Bokhoven, H. A1 - Boomsma, D. I. A1 - Brodaty, H. A1 - Brouwer, R. M. A1 - Brunner, H. G. A1 - Buckner, R. L. A1 - Buitelaar, J. K. A1 - Bulayeva, K. B. A1 - Cahn, W. A1 - Calhoun, V. D. A1 - Cannon, D. M. A1 - Cavalleri, G. L. A1 - Cheng, C. Y. A1 - Cichon, S. A1 - Cookson, M. R. A1 - Corvin, A. A1 - Crespo-Facorro, B. A1 - Curran, J. E. A1 - Czisch, M. A1 - Dale, A. M. A1 - Davies, G. E. A1 - de Craen, A. J. M. A1 - de Geus, E. J. C. A1 - De Jager, P. L. A1 - de Zubicaray, G. I. A1 - Deary, I. J. A1 - Debette, S. A1 - DeCarli, C. A1 - Delanty, N. A1 - Depondt, C. A1 - DeStefano, A. A1 - Dillman, A. A1 - Djurovic, S. A1 - Donohoe, G. A1 - Drevets, W. C. A1 - Duggirala, R. A1 - Dyer, T. D. A1 - Enzinger, C. A1 - Erk, S. A1 - Espeseth, T. A1 - Fedko, I. O. A1 - Fern?ndez, G. A1 - Ferrucci, L. A1 - Fisher, S. E. A1 - Fleischman, D. A. A1 - Ford, I. A1 - Fornage, M. A1 - Foroud, T. M. A1 - Fox, P. T. A1 - Francks, C. A1 - Fukunaga, M. A1 - Gibbs, J. R. A1 - Glahn, D. C. A1 - Gollub, R. L. A1 - G?ring, H. H. H. A1 - Green, R. C. A1 - Gruber, O. A1 - Gudnason, V. A1 - Guelfi, S. A1 - H?berg, A. K. A1 - Hansell, N. K. A1 - Hardy, J. A1 - Hartman, C. A. A1 - Hashimoto, R. A1 - Hegenscheid, K. A1 - Heinz, A. A1 - Le Hellard, S. A1 - Hernandez, D. G. A1 - Heslenfeld, D. J. A1 - Ho, B. C. A1 - Hoekstra, P. J. A1 - Hoffmann, W. A1 - Hofman, A. A1 - Holsboer, F. A1 - Homuth, G. A1 - Hosten, N. A1 - Hottenga, J. J. A1 - Huentelman, M. A1 - Hulshoff Pol, H. E. A1 - Ikeda, M. A1 - Jack, C. R. A1 - Jenkinson, M. A1 - Johnson, R. A1 - J?nsson, E. G. A1 - Jukema, J. W. A1 - Kahn, R. S. A1 - Kanai, R. A1 - Kloszewska, I. A1 - Knopman, D. S. A1 - Kochunov, P. A1 - Kwok, J. B. A1 - Lawrie, S. M. A1 - Lema?tre, H. A1 - Liu, X. A1 - Longo, D. L. A1 - Lopez, O. L. A1 - Lovestone, S. A1 - Martinez, O. A1 - Martinot, J. L. A1 - Mattay, V. S. A1 - McDonald, C. A1 - McIntosh, A. M. A1 - McMahon, F. J. A1 - McMahon, K. L. A1 - Mecocci, P. A1 - Melle, I. A1 - Meyer-Lindenberg, A. A1 - Mohnke, S. A1 - Montgomery, G. W. A1 - Morris, D. W. A1 - Mosley, T. H. A1 - M?hleisen, T. W. A1 - M?ller-Myhsok, B. A1 - Nalls, M. A. A1 - Nauck, M. A1 - Nichols, T. E. A1 - Niessen, W. J. A1 - N?then, M. M. A1 - Nyberg, L. A1 - Ohi, K. A1 - Olvera, R. L. A1 - Ophoff, R. A. A1 - Pandolfo, M. A1 - Paus, T. A1 - Pausova, Z. A1 - Penninx, B. W. J. H. A1 - Pike, G. B. A1 - Potkin, S. G. A1 - Psaty, B. M. A1 - Reppermund, S. A1 - Rietschel, M. A1 - Roffman, J. L. A1 - Romanczuk-Seiferth, N. A1 - Rotter, J. I. A1 - Ryten, M. A1 - Sacco, R. L. A1 - Sachdev, P. S. A1 - Saykin, A. J. A1 - Schmidt, R. A1 - Schmidt, H. A1 - Schofield, P. R. A1 - Sigursson, S. A1 - Simmons, A. A1 - Singleton, A. A1 - Sisodiya, S. M. A1 - Smith, C. A1 - Smoller, J. W. A1 - Soininen, H. A1 - Steen, V. M. A1 - Stott, D. J. A1 - Sussmann, J. E. A1 - Thalamuthu, A. A1 - Toga, A. W. A1 - Traynor, B. J. A1 - Troncoso, J. A1 - Tsolaki, M. A1 - Tzourio, C. A1 - Uitterlinden, A. G. A1 - Hern?ndez, M. C. V. A1 - Van der Brug, M. A1 - van der Lugt, A. A1 - Van der Wee, N. J. A. A1 - van Haren, N. E. M. A1 - van 't Ent, D. A1 - van Tol, M. J. A1 - Vardarajan, B. N. A1 - Vellas, B. A1 - Veltman, D. J. A1 - V?lzke, H. A1 - Walter, H. A1 - Wardlaw, J. M. A1 - Wassink, T. H. A1 - Weale, M. E. A1 - Weinberger, D. R. A1 - Weiner, M. W. A1 - Wen, W. A1 - Westman, E. A1 - White, T. A1 - Wong, T. Y. A1 - Wright, C. B. A1 - Zielke, R. H. A1 - Zonderman, A. B. A1 - Martin, N. G. A1 - van Duijn, C. M. A1 - Wright, M. J. A1 - Longstreth, W. T. A1 - Schumann, G. A1 - Grabe, H. J. A1 - Franke, B. A1 - Launer, L. J. A1 - Medland, S. E. A1 - Seshadri, S. A1 - Thompson, P. M. A1 - Ikram, M. A. AB - The 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. VL - 8 ER - TY - JOUR T1 - PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kent, Shia T A1 - Rosenson, Robert S A1 - Avery, Christy L A1 - Chen, Yii-der I A1 - Correa, Adolfo A1 - Cummings, Steven R A1 - Cupples, L Adrienne A1 - Cushman, Mary A1 - Evans, Daniel S A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Howard, George A1 - Irvin, Marguerite R A1 - Judd, Suzanne E A1 - Jukema, J Wouter A1 - Lange, Leslie A1 - Levitan, Emily B A1 - Li, Xiaohui A1 - Liu, Yongmei A1 - Post, Wendy S A1 - Postmus, Iris A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Safford, Monika M A1 - Sitlani, Colleen M A1 - Smith, Albert V A1 - Stewart, James D A1 - Trompet, Stella A1 - Sun, Fangui A1 - Vasan, Ramachandran S A1 - Woolley, J Michael A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Wilson, James G A1 - Muntner, Paul AB -

BACKGROUND: 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.

VL - 10 IS - 4 ER - TY - JOUR T1 - Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. JF - Pharmacogenomics J Y1 - 2017 A1 - Seyerle, A A A1 - Sitlani, C M A1 - Noordam, R A1 - Gogarten, S M A1 - Li, J A1 - Li, X A1 - Evans, D S A1 - Sun, F A1 - Laaksonen, M A A1 - Isaacs, A A1 - Kristiansson, K A1 - Highland, H M A1 - Stewart, J D A1 - Harris, T B A1 - Trompet, S A1 - Bis, J C A1 - Peloso, G M A1 - Brody, J A A1 - Broer, L A1 - Busch, E L A1 - Duan, Q A1 - Stilp, A M A1 - O'Donnell, C J A1 - Macfarlane, P W A1 - Floyd, J S A1 - Kors, J A A1 - Lin, H J A1 - Li-Gao, R A1 - Sofer, T A1 - Méndez-Giráldez, R A1 - Cummings, S R A1 - Heckbert, S R A1 - Hofman, A A1 - Ford, I A1 - Li, Y A1 - Launer, L J A1 - Porthan, K A1 - Newton-Cheh, C A1 - Napier, M D A1 - Kerr, K F A1 - Reiner, A P A1 - Rice, K M A1 - Roach, J A1 - Buckley, B M A1 - Soliman, E Z A1 - de Mutsert, R A1 - Sotoodehnia, N A1 - Uitterlinden, A G A1 - North, K E A1 - Lee, C R A1 - Gudnason, V A1 - Stürmer, T A1 - Rosendaal, F R A1 - Taylor, K D A1 - Wiggins, K L A1 - Wilson, J G A1 - Chen, Y-DI A1 - Kaplan, R C A1 - Wilhelmsen, K A1 - Cupples, L A A1 - Salomaa, V A1 - van Duijn, C A1 - Jukema, J W A1 - Liu, Y A1 - Mook-Kanamori, D O A1 - Lange, L A A1 - Vasan, R S A1 - Smith, A V A1 - Stricker, B H A1 - Laurie, C C A1 - Rotter, J I A1 - Whitsel, E A A1 - Psaty, B M A1 - Avery, C L AB -

Thiazide 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.

ER - TY - JOUR T1 - Predictors and outcomes of heart failure with mid-range ejection fraction. JF - Eur J Heart Fail Y1 - 2017 A1 - Bhambhani, Vijeta A1 - Kizer, Jorge R A1 - Lima, João A C A1 - van der Harst, Pim A1 - Bahrami, Hossein A1 - Nayor, Matthew A1 - de Filippi, Christopher R A1 - Enserro, Danielle A1 - Blaha, Michael J A1 - Cushman, Mary A1 - Wang, Thomas J A1 - Gansevoort, Ron T A1 - Fox, Caroline S A1 - Gaggin, Hanna K A1 - Kop, Willem J A1 - Liu, Kiang A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Lee, Douglas S A1 - Brouwers, Frank P A1 - Hillege, Hans L A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Chan, Cheeling A1 - Allison, Matthew A1 - Gardin, Julius M A1 - Januzzi, James L A1 - Levy, Daniel A1 - Herrington, David M A1 - van Gilst, Wiek H A1 - Bertoni, Alain G A1 - Larson, Martin G A1 - de Boer, Rudolf A A1 - Gottdiener, John S A1 - Shah, Sanjiv J A1 - Ho, Jennifer E AB -

AIMS: 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.

ER - TY - JOUR T1 - Predictors of incident epilepsy in older adults: The Cardiovascular Health Study. JF - Neurology Y1 - 2017 A1 - Choi, Hyunmi A1 - Pack, Alison A1 - Elkind, Mitchell S V A1 - Longstreth, W T A1 - Ton, Thanh G N A1 - Onchiri, Frankline AB -

OBJECTIVE: 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.

VL - 88 IS - 9 ER - TY - JOUR T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. JF - Nat Genet Y1 - 2017 A1 - Sims, Rebecca A1 - van der Lee, Sven J A1 - Naj, Adam C A1 - Bellenguez, Céline A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Kunkle, Brian W A1 - Boland, Anne A1 - Raybould, Rachel A1 - Bis, Joshua C A1 - Martin, Eden R A1 - Grenier-Boley, Benjamin A1 - Heilmann-Heimbach, Stefanie A1 - Chouraki, Vincent A1 - Kuzma, Amanda B A1 - Sleegers, Kristel A1 - Vronskaya, Maria A1 - Ruiz, Agustin A1 - Graham, Robert R A1 - Olaso, Robert A1 - Hoffmann, Per A1 - Grove, Megan L A1 - Vardarajan, Badri N A1 - Hiltunen, Mikko A1 - Nöthen, Markus M A1 - White, Charles C A1 - Hamilton-Nelson, Kara L A1 - Epelbaum, Jacques A1 - Maier, Wolfgang A1 - Choi, Seung-Hoan A1 - Beecham, Gary W A1 - Dulary, Cécile A1 - Herms, Stefan A1 - Smith, Albert V A1 - Funk, Cory C A1 - Derbois, Céline A1 - Forstner, Andreas J A1 - Ahmad, Shahzad A1 - Li, Hongdong A1 - Bacq, Delphine A1 - Harold, Denise A1 - Satizabal, Claudia L A1 - Valladares, Otto A1 - Squassina, Alessio A1 - Thomas, Rhodri A1 - Brody, Jennifer A A1 - Qu, Liming A1 - Sánchez-Juan, Pascual A1 - Morgan, Taniesha A1 - Wolters, Frank J A1 - Zhao, Yi A1 - Garcia, Florentino Sanchez A1 - Denning, Nicola A1 - Fornage, Myriam A1 - Malamon, John A1 - Naranjo, Maria Candida Deniz A1 - Majounie, Elisa A1 - Mosley, Thomas H A1 - Dombroski, Beth A1 - Wallon, David A1 - Lupton, Michelle K A1 - Dupuis, Josée A1 - Whitehead, Patrice A1 - Fratiglioni, Laura A1 - Medway, Christopher A1 - Jian, Xueqiu A1 - Mukherjee, Shubhabrata A1 - Keller, Lina A1 - Brown, Kristelle A1 - Lin, Honghuang A1 - Cantwell, Laura B A1 - Panza, Francesco A1 - McGuinness, Bernadette A1 - Moreno-Grau, Sonia A1 - Burgess, Jeremy D A1 - Solfrizzi, Vincenzo A1 - Proitsi, Petra A1 - Adams, Hieab H A1 - Allen, Mariet A1 - Seripa, Davide A1 - Pastor, Pau A1 - Cupples, L Adrienne A1 - Price, Nathan D A1 - Hannequin, Didier A1 - Frank-García, Ana A1 - Levy, Daniel A1 - Chakrabarty, Paramita A1 - Caffarra, Paolo A1 - Giegling, Ina A1 - Beiser, Alexa S A1 - Giedraitis, Vilmantas A1 - Hampel, Harald A1 - Garcia, Melissa E A1 - Wang, Xue A1 - Lannfelt, Lars A1 - Mecocci, Patrizia A1 - Eiriksdottir, Gudny A1 - Crane, Paul K A1 - Pasquier, Florence A1 - Boccardi, Virginia A1 - Henández, Isabel A1 - Barber, Robert C A1 - Scherer, Martin A1 - Tarraga, Lluis A1 - Adams, Perrie M A1 - Leber, Markus A1 - Chen, Yuning A1 - Albert, Marilyn S A1 - Riedel-Heller, Steffi A1 - Emilsson, Valur A1 - Beekly, Duane A1 - Braae, Anne A1 - Schmidt, Reinhold A1 - Blacker, Deborah A1 - Masullo, Carlo A1 - Schmidt, Helena A1 - Doody, Rachelle S A1 - Spalletta, Gianfranco A1 - Jr, W T Longstreth A1 - Fairchild, Thomas J A1 - Bossù, Paola A1 - Lopez, Oscar L A1 - Frosch, Matthew P A1 - Sacchinelli, Eleonora A1 - Ghetti, Bernardino A1 - Yang, Qiong A1 - Huebinger, Ryan M A1 - Jessen, Frank A1 - Li, Shuo A1 - Kamboh, M Ilyas A1 - Morris, John A1 - Sotolongo-Grau, Oscar A1 - Katz, Mindy J A1 - Corcoran, Chris A1 - Dunstan, Melanie A1 - Braddel, Amy A1 - Thomas, Charlene A1 - Meggy, Alun A1 - Marshall, Rachel A1 - Gerrish, Amy A1 - Chapman, Jade A1 - Aguilar, Miquel A1 - Taylor, Sarah A1 - Hill, Matt A1 - Fairén, Mònica Díez A1 - Hodges, Angela A1 - Vellas, Bruno A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Daniilidou, Makrina A1 - Uphill, James A1 - Patel, Yogen A1 - Hughes, Joseph T A1 - Lord, Jenny A1 - Turton, James A1 - Hartmann, Annette M A1 - Cecchetti, Roberta A1 - Fenoglio, Chiara A1 - Serpente, Maria A1 - Arcaro, Marina A1 - Caltagirone, Carlo A1 - Orfei, Maria Donata A1 - Ciaramella, Antonio A1 - Pichler, Sabrina A1 - Mayhaus, Manuel A1 - Gu, Wei A1 - Lleo, Alberto A1 - Fortea, Juan A1 - Blesa, Rafael A1 - Barber, Imelda S A1 - Brookes, Keeley A1 - Cupidi, Chiara A1 - Maletta, Raffaele Giovanni A1 - Carrell, David A1 - Sorbi, Sandro A1 - Moebus, Susanne A1 - Urbano, Maria A1 - Pilotto, Alberto A1 - Kornhuber, Johannes A1 - Bosco, Paolo A1 - Todd, Stephen A1 - Craig, David A1 - Johnston, Janet A1 - Gill, Michael A1 - Lawlor, Brian A1 - Lynch, Aoibhinn A1 - Fox, Nick C A1 - Hardy, John A1 - Albin, Roger L A1 - Apostolova, Liana G A1 - Arnold, Steven E A1 - Asthana, Sanjay A1 - Atwood, Craig S A1 - Baldwin, Clinton T A1 - Barnes, Lisa L A1 - Barral, Sandra A1 - Beach, Thomas G A1 - Becker, James T A1 - Bigio, Eileen H A1 - Bird, Thomas D A1 - Boeve, Bradley F A1 - Bowen, James D A1 - Boxer, Adam A1 - Burke, James R A1 - Burns, Jeffrey M A1 - Buxbaum, Joseph D A1 - Cairns, Nigel J A1 - Cao, Chuanhai A1 - Carlson, Chris S A1 - Carlsson, Cynthia M A1 - Carney, Regina M A1 - Carrasquillo, Minerva M A1 - Carroll, Steven L A1 - Diaz, Carolina Ceballos A1 - Chui, Helena C A1 - Clark, David G A1 - Cribbs, David H A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Dick, Malcolm A1 - Duara, Ranjan A1 - Evans, Denis A A1 - Faber, Kelley M A1 - Fallon, Kenneth B A1 - Fardo, David W A1 - Farlow, Martin R A1 - Ferris, Steven A1 - Foroud, Tatiana M A1 - Galasko, Douglas R A1 - Gearing, Marla A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Graff-Radford, Neill R A1 - Green, Robert C A1 - Growdon, John H A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Honig, Lawrence S A1 - Huentelman, Matthew J A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Jarvik, Gail P A1 - Abner, Erin A1 - Jin, Lee-Way A1 - Jun, Gyungah A1 - Karydas, Anna A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Kowall, Neil W A1 - Kramer, Joel H A1 - LaFerla, Frank M A1 - Lah, James J A1 - Leverenz, James B A1 - Levey, Allan I A1 - Li, Ge A1 - Lieberman, Andrew P A1 - Lunetta, Kathryn L A1 - Lyketsos, Constantine G A1 - Marson, Daniel C A1 - Martiniuk, Frank A1 - Mash, Deborah C A1 - Masliah, Eliezer A1 - McCormick, Wayne C A1 - McCurry, Susan M A1 - McDavid, Andrew N A1 - McKee, Ann C A1 - Mesulam, Marsel A1 - Miller, Bruce L A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Morris, John C A1 - Murrell, Jill R A1 - Myers, Amanda J A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Pankratz, Vernon S A1 - Parisi, Joseph E A1 - Paulson, Henry L A1 - Perry, William A1 - Peskind, Elaine A1 - Pierce, Aimee A1 - Poon, Wayne W A1 - Potter, Huntington A1 - Quinn, Joseph F A1 - Raj, Ashok A1 - Raskind, Murray A1 - Reisberg, Barry A1 - Reitz, Christiane A1 - Ringman, John M A1 - Roberson, Erik D A1 - Rogaeva, Ekaterina A1 - Rosen, Howard J A1 - Rosenberg, Roger N A1 - Sager, Mark A A1 - Saykin, Andrew J A1 - Schneider, Julie A A1 - Schneider, Lon S A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tanzi, Rudolph E A1 - Thornton-Wells, Tricia A A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Garzia, Fabienne A1 - Golamaully, Feroze A1 - Septier, Gislain A1 - Engelborghs, Sebastien A1 - Vandenberghe, Rik A1 - De Deyn, Peter P A1 - Fernadez, Carmen Muñoz A1 - Benito, Yoland Aladro A1 - Thonberg, Håkan A1 - Forsell, Charlotte A1 - Lilius, Lena A1 - Kinhult-Ståhlbom, Anne A1 - Kilander, Lena A1 - Brundin, RoseMarie A1 - Concari, Letizia A1 - Helisalmi, Seppo A1 - Koivisto, Anne Maria A1 - Haapasalo, Annakaisa A1 - Dermecourt, Vincent A1 - Fiévet, Nathalie A1 - Hanon, Olivier A1 - Dufouil, Carole A1 - Brice, Alexis A1 - Ritchie, Karen A1 - Dubois, Bruno A1 - Himali, Jayanadra J A1 - Keene, C Dirk A1 - Tschanz, JoAnn A1 - Fitzpatrick, Annette L A1 - Kukull, Walter A A1 - Norton, Maria A1 - Aspelund, Thor A1 - Larson, Eric B A1 - Munger, Ron A1 - Rotter, Jerome I A1 - Lipton, Richard B A1 - Bullido, María J A1 - Hofman, Albert A1 - Montine, Thomas J A1 - Coto, Eliecer A1 - Boerwinkle, Eric A1 - Petersen, Ronald C A1 - Alvarez, Victoria A1 - Rivadeneira, Fernando A1 - Reiman, Eric M A1 - Gallo, Maura A1 - O'Donnell, Christopher J A1 - Reisch, Joan S A1 - Bruni, Amalia Cecilia A1 - Royall, Donald R A1 - Dichgans, Martin A1 - Sano, Mary A1 - Galimberti, Daniela A1 - St George-Hyslop, Peter A1 - Scarpini, Elio A1 - Tsuang, Debby W A1 - Mancuso, Michelangelo A1 - Bonuccelli, Ubaldo A1 - Winslow, Ashley R A1 - Daniele, Antonio A1 - Wu, Chuang-Kuo A1 - Peters, Oliver A1 - Nacmias, Benedetta A1 - Riemenschneider, Matthias A1 - Heun, Reinhard A1 - Brayne, Carol A1 - Rubinsztein, David C A1 - Bras, Jose A1 - Guerreiro, Rita A1 - Al-Chalabi, Ammar A1 - Shaw, Christopher E A1 - Collinge, John A1 - Mann, David A1 - Tsolaki, Magda A1 - Clarimon, Jordi A1 - Sussams, Rebecca A1 - Lovestone, Simon A1 - O'Donovan, Michael C A1 - Owen, Michael J A1 - Behrens, Timothy W A1 - Mead, Simon A1 - Goate, Alison M A1 - Uitterlinden, André G A1 - Holmes, Clive A1 - Cruchaga, Carlos A1 - Ingelsson, Martin A1 - Bennett, David A A1 - Powell, John A1 - Golde, Todd E A1 - Graff, Caroline A1 - De Jager, Philip L A1 - Morgan, Kevin A1 - Ertekin-Taner, Nilufer A1 - Combarros, Onofre A1 - Psaty, Bruce M A1 - Passmore, Peter A1 - Younkin, Steven G A1 - Berr, Claudine A1 - Gudnason, Vilmundur A1 - Rujescu, Dan A1 - Dickson, Dennis W A1 - Dartigues, Jean-François A1 - DeStefano, Anita L A1 - Ortega-Cubero, Sara A1 - Hakonarson, Hakon A1 - Campion, Dominique A1 - Boada, Merce A1 - Kauwe, John Keoni A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - Ikram, M Arfan A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Tzourio, Christophe A1 - Launer, Lenore J A1 - Escott-Price, Valentina A1 - Mayeux, Richard A1 - Deleuze, Jean-Francois A1 - Amin, Najaf A1 - Holmans, Peter A A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Lambert, Jean-Charles A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Schellenberg, Gerard D KW - Adaptor Proteins, Signal Transducing KW - Alzheimer Disease KW - Amino Acid Sequence KW - Case-Control Studies KW - Exome KW - Gene Expression Profiling KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Immunity, Innate KW - Linkage Disequilibrium KW - Membrane Glycoproteins KW - Microglia KW - Odds Ratio KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Protein Interaction Maps KW - Receptors, Immunologic KW - Sequence Homology, Amino Acid AB -

We 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.

VL - 49 IS - 9 ER - TY - JOUR T1 - Rare coding variants pinpoint genes that control human hematological traits. JF - PLoS Genet Y1 - 2017 A1 - Mousas, Abdou A1 - Ntritsos, Georgios A1 - Chen, Ming-Huei A1 - Song, Ci A1 - Huffman, Jennifer E A1 - Tzoulaki, Ioanna A1 - Elliott, Paul A1 - Psaty, Bruce M A1 - Auer, Paul L A1 - Johnson, Andrew D A1 - Evangelou, Evangelos A1 - Lettre, Guillaume A1 - Reiner, Alexander P KW - Asthma KW - Databases, Genetic KW - Endometriosis KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Interleukin-33 KW - Linear Models KW - Logistic Models KW - Male KW - Mutation, Missense KW - Phenotype KW - Plasminogen KW - Platelet Count KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Protein Splicing KW - Rhinitis, Allergic KW - Sequence Analysis, DNA AB -

The 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.

VL - 13 IS - 8 ER - TY - JOUR T1 - The Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals. JF - Clin J Am Soc Nephrol Y1 - 2017 A1 - Hughes-Austin, Jan M A1 - Rifkin, Dena E A1 - Beben, Tomasz A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Deo, Rajat A1 - Hoofnagle, Andrew N A1 - Homma, Shunichi A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Psaty, Bruce M A1 - de Boer, Ian H A1 - Kestenbaum, Bryan A1 - Shlipak, Michael G A1 - Ix, Joachim H AB -

BACKGROUND 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.

VL - 12 IS - 2 ER - TY - JOUR T1 - Relation 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). JF - Am J Cardiol Y1 - 2017 A1 - Maurer, Mathew S A1 - Koh, William J H A1 - Bartz, Traci M A1 - Vullaganti, Sirish A1 - Barasch, Eddy A1 - Gardin, Julius M A1 - Gottdiener, John S A1 - Psaty, Bruce M A1 - Kizer, Jorge R AB -

We 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.

VL - 119 IS - 6 ER - TY - JOUR T1 - Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure. JF - J Am Coll Cardiol Y1 - 2017 A1 - Pandey, Ambarish A1 - LaMonte, Michael A1 - Klein, Liviu A1 - Ayers, Colby A1 - Psaty, Bruce M A1 - Eaton, Charles B A1 - Allen, Norrina B A1 - de Lemos, James A A1 - Carnethon, Mercedes A1 - Greenland, Philip A1 - Berry, Jarett D AB -

BACKGROUND: 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.

VL - 69 IS - 9 ER - TY - JOUR T1 - REPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES CARDIOVASCULAR DISEASE RISK PREDICTION: AN INDIVIDUAL-PARTICIPANT-DATA META-ANALYSIS. JF - Am J Epidemiol Y1 - 2017 A1 - Paige, Ellie A1 - Barrett, Jessica A1 - Pennells, Lisa A1 - Sweeting, Michael A1 - Willeit, Peter A1 - Di Angelantonio, Emanuele A1 - Gudnason, Vilmundur A1 - Nordestgaard, Børge G A1 - Psaty, Bruce M A1 - Goldbourt, Uri A1 - Best, Lyle G A1 - Assmann, Gerd A1 - Salonen, Jukka T A1 - Nietert, Paul J A1 - Verschuren, Wm Monique A1 - Brunner, Eric J A1 - Kronmal, Richard A A1 - Salomaa, Veikko A1 - Bakker, Stephan Jl A1 - Dagenais, Gilles R A1 - Sato, Shinichi A1 - Jansson, Jan-Håkan A1 - Willeit, Johann A1 - Onat, Altan A1 - de la Cámara, Agustin Gómez A1 - Roussel, Ronan A1 - Völzke, Henry A1 - Dankner, Rachel A1 - Tipping, Robert W A1 - Meade, Tom W A1 - Donfrancesco, Chiara A1 - Kuller, Lewis H A1 - Peters, Annette A1 - Gallacher, John A1 - Kromhout, Daan A1 - Iso, Hiroyasu A1 - Knuiman, Matthew A1 - Casiglia, Edoardo A1 - Kavousi, Maryam A1 - Palmieri, Luigi A1 - Sundström, Johan A1 - Davis, Barry R A1 - Njølstad, Inger A1 - Couper, David A1 - Danesh, John A1 - Thompson, Simon G A1 - Wood, Angela AB -

The 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.

ER - TY - JOUR T1 - Short telomere length is associated with impaired cognitive performance in European ancestry cohorts. JF - Transl Psychiatry Y1 - 2017 A1 - Hägg, S A1 - Zhan, Y A1 - Karlsson, R A1 - Gerritsen, L A1 - Ploner, A A1 - van der Lee, S J A1 - Broer, L A1 - Deelen, J A1 - Marioni, R E A1 - Wong, A A1 - Lundquist, A A1 - Zhu, G A1 - Hansell, N K A1 - Sillanpää, E A1 - Fedko, I O A1 - Amin, N A A1 - Beekman, M A1 - de Craen, A J M A1 - Degerman, S A1 - Harris, S E A1 - Kan, K-J A1 - Martin-Ruiz, C M A1 - Montgomery, G W A1 - Adolfsson, A N A1 - Reynolds, C A A1 - Samani, N J A1 - Suchiman, H E D A1 - Viljanen, A A1 - von Zglinicki, T A1 - Wright, M J A1 - Hottenga, J-J A1 - Boomsma, D I A1 - Rantanen, T A1 - Kaprio, J A A1 - Nyholt, D R A1 - Martin, N G A1 - Nyberg, L A1 - Adolfsson, R A1 - Kuh, D A1 - Starr, J M A1 - Deary, I J A1 - Slagboom, P E A1 - van Duijn, C M A1 - Codd, V A1 - Pedersen, N L KW - Adult KW - Aged KW - Apolipoprotein E4 KW - Cognitive Dysfunction KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Carrier Screening KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Neuropsychological Tests KW - Psychometrics KW - Statistics as Topic KW - Telomere AB -

The 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.

VL - 7 IS - 4 ER - TY - JOUR T1 - Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. JF - PLoS Genet Y1 - 2017 A1 - Liang, Jingjing A1 - Le, Thu H A1 - Edwards, Digna R Velez A1 - Tayo, Bamidele O A1 - Gaulton, Kyle J A1 - Smith, Jennifer A A1 - Lu, Yingchang A1 - Jensen, Richard A A1 - Chen, Guanjie A1 - Yanek, Lisa R A1 - Schwander, Karen A1 - Tajuddin, Salman M A1 - Sofer, Tamar A1 - Kim, Wonji A1 - Kayima, James A1 - McKenzie, Colin A A1 - Fox, Ervin A1 - Nalls, Michael A A1 - Young, J Hunter A1 - Sun, Yan V A1 - Lane, Jacqueline M A1 - Cechova, Sylvia A1 - Zhou, Jie A1 - Tang, Hua A1 - Fornage, Myriam A1 - Musani, Solomon K A1 - Wang, Heming A1 - Lee, Juyoung A1 - Adeyemo, Adebowale A1 - Dreisbach, Albert W A1 - Forrester, Terrence A1 - Chu, Pei-Lun A1 - Cappola, Anne A1 - Evans, Michele K A1 - Morrison, Alanna C A1 - Martin, Lisa W A1 - Wiggins, Kerri L A1 - Hui, Qin A1 - Zhao, Wei A1 - Jackson, Rebecca D A1 - Ware, Erin B A1 - Faul, Jessica D A1 - Reiner, Alex P A1 - Bray, Michael A1 - Denny, Joshua C A1 - Mosley, Thomas H A1 - Palmas, Walter A1 - Guo, Xiuqing A1 - Papanicolaou, George J A1 - Penman, Alan D A1 - Polak, Joseph F A1 - Rice, Kenneth A1 - Taylor, Ken D A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Liu, Kiang A1 - Risch, Neil A1 - Hunt, Steven C A1 - Kooperberg, Charles A1 - Zonderman, Alan B A1 - Laurie, Cathy C A1 - Becker, Diane M A1 - Cai, Jianwen A1 - Loos, Ruth J F A1 - Psaty, Bruce M A1 - Weir, David R A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Won, Sungho A1 - Edwards, Todd L A1 - Redline, Susan A1 - Cooper, Richard S A1 - Rao, D C A1 - Rotter, Jerome I A1 - Rotimi, Charles A1 - Levy, Daniel A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Franceschini, Nora KW - African Americans KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Blood Pressure KW - Cadherins KW - Case-Control Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Membrane Proteins KW - Mice KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide AB -

Hypertension 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.

VL - 13 IS - 5 ER - TY - JOUR T1 - Soluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study. JF - J Bone Miner Res Y1 - 2017 A1 - Stojanović, Danijela A1 - Bůzková, Petra A1 - Mukamal, Kenneth J A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Fink, Howard A A1 - Cauley, Jane A A1 - Wallace, Erin A1 - Curtis, Lesley H A1 - Hirsch, Calvin A1 - Budoff, Matthew A1 - Li, Dong A1 - Young, Rebekah A1 - Jalal, Diana A1 - Delaney, Joseph Ac AB -

Several 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.

ER - TY - JOUR T1 - Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis. JF - J Thromb Haemost Y1 - 2017 A1 - Roetker, N S A1 - Armasu, S M A1 - Pankow, J S A1 - Lutsey, P L A1 - Tang, W A1 - Rosenberg, M A A1 - Palmer, T M A1 - MacLehose, R F A1 - Heckbert, S R A1 - Cushman, M A1 - de Andrade, M A1 - Folsom, A R AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Telomeres and the natural lifespan limit in humans. JF - Aging (Albany NY) Y1 - 2017 A1 - Steenstrup, Troels A1 - Kark, Jeremy D A1 - Verhulst, Simon A1 - Thinggaard, Mikael A1 - Hjelmborg, Jacob V B A1 - Dalgård, Christine A1 - Kyvik, Kirsten Ohm A1 - Christiansen, Lene A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Petersen, Inge A1 - Kimura, Masayuki A1 - Benetos, Athanase A1 - Labat, Carlos A1 - Sinnreich, Ronit A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Hunt, Steven C A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Barbieri, Michelangela A1 - Paolisso, Giuseppe A1 - Gadalla, Shahinaz M A1 - Savage, Sharon A A1 - Christensen, Kaare A1 - Yashin, Anatoliy I A1 - Arbeev, Konstantin G A1 - Aviv, Abraham AB -

An 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.

VL - 9 IS - 4 ER - TY - JOUR T1 - Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation. JF - Circulation Y1 - 2017 A1 - Baumgartner, Christine A1 - da Costa, Bruno R A1 - Collet, Tinh-Hai A1 - Feller, Martin A1 - Floriani, Carmen A1 - Bauer, Douglas C A1 - Cappola, Anne R A1 - Heckbert, Susan R A1 - Ceresini, Graziano A1 - Gussekloo, Jacobijn A1 - den Elzen, Wendy P J A1 - Peeters, Robin P A1 - Luben, Robert A1 - Völzke, Henry A1 - Dörr, Marcus A1 - Walsh, John P A1 - Bremner, Alexandra A1 - Iacoviello, Massimo A1 - Macfarlane, Peter A1 - Heeringa, Jan A1 - Stott, David J A1 - Westendorp, Rudi G J A1 - Khaw, Kay-Tee A1 - Magnani, Jared W A1 - Aujesky, Drahomir A1 - Rodondi, Nicolas KW - Adult KW - Aged KW - Aged, 80 and over KW - Asymptomatic Diseases KW - Atrial Fibrillation KW - Biomarkers KW - Chi-Square Distribution KW - Female KW - Humans KW - Hypothyroidism KW - Incidence KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Thyroid Function Tests KW - Thyroid Gland KW - Thyrotropin KW - Thyroxine KW - Time Factors KW - Young Adult AB -

BACKGROUND: 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.

VL - 136 IS - 22 ER - TY - JOUR T1 - Trajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2017 A1 - Sanders, Jason L A1 - Guo, Wensheng A1 - O'Meara, Ellen S A1 - Kaplan, Robert C A1 - Pollak, Michael N A1 - Bartz, Traci M A1 - Newman, Anne B A1 - Fried, Linda P A1 - Cappola, Anne R AB -

Background: 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.

ER - TY - JOUR T1 - Trans-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. JF - Hum Genet Y1 - 2017 A1 - Fernandez-Rhodes, Lindsay A1 - Gong, Jian A1 - Haessler, Jeffrey A1 - Franceschini, Nora A1 - Graff, Mariaelisa A1 - Nishimura, Katherine K A1 - Wang, Yujie A1 - Highland, Heather M A1 - Yoneyama, Sachiko A1 - Bush, William S A1 - Goodloe, Robert A1 - Ritchie, Marylyn D A1 - Crawford, Dana A1 - Gross, Myron A1 - Fornage, Myriam A1 - Bůzková, Petra A1 - Tao, Ran A1 - Isasi, Carmen A1 - Avilés-Santa, Larissa A1 - Daviglus, Martha A1 - Mackey, Rachel H A1 - Houston, Denise A1 - Gu, C Charles A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Lim, Unhee A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Schumacher, Fredrick A1 - Wilkens, Lynne A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J L A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Lee, Wen-Jane A1 - Hai, Yang A1 - Hung, Yi-Jen A1 - Absher, Devin A1 - Wu, I-Chien A1 - Taylor, Kent D A1 - Lee, I-Te A1 - Liu, Yeheng A1 - Wang, Tzung-Dau A1 - Quertermous, Thomas A1 - Juang, Jyh-Ming J A1 - Rotter, Jerome I A1 - Assimes, Themistocles A1 - Hsiung, Chao A A1 - Chen, Yii-Der Ida A1 - Prentice, Ross A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Smokowski, Paul A1 - Robinson, Whitney R A1 - Gordon-Larsen, Penny A1 - Li, Rongling A1 - Hindorff, Lucia A1 - Buyske, Steven A1 - Matise, Tara C A1 - Peters, Ulrike A1 - North, Kari E KW - Body Mass Index KW - Ethnic Groups KW - Genetics, Population KW - Humans KW - Obesity AB -

Most 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.

VL - 136 IS - 6 ER - TY - JOUR T1 - Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. JF - Eur J Epidemiol Y1 - 2017 A1 - Chibnik, Lori B A1 - Wolters, Frank J A1 - Bäckman, Kristoffer A1 - Beiser, Alexa A1 - Berr, Claudine A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bos, Daniel A1 - Brayne, Carol A1 - Dartigues, Jean-François A1 - Darweesh, Sirwan K L A1 - Debette, Stephanie A1 - Davis-Plourde, Kendra L A1 - Dufouil, Carole A1 - Fornage, Myriam A1 - Grasset, Leslie A1 - Gudnason, Vilmundur A1 - Hadjichrysanthou, Christoforos A1 - Helmer, Catherine A1 - Ikram, M Arfan A1 - Ikram, M Kamran A1 - Kern, Silke A1 - Kuller, Lewis H A1 - Launer, Lenore A1 - Lopez, Oscar L A1 - Matthews, Fiona A1 - Meirelles, Osorio A1 - Mosley, Thomas A1 - Ower, Alison A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Seshadri, Sudha A1 - Skoog, Ingmar A1 - Stephan, Blossom C M A1 - Tzourio, Christophe A1 - Waziry, Reem A1 - Wong, Mei Mei A1 - Zettergren, Anna A1 - Hofman, Albert AB -

Several 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.

VL - 32 IS - 10 ER - TY - JOUR T1 - Visit-to-Visit Blood Pressure Variability and Mortality and Cardiovascular Outcomes Among Older Adults: The Health, Aging, and Body Composition Study. JF - Am J Hypertens Y1 - 2017 A1 - Wu, Chenkai A1 - Shlipak, Michael G A1 - Stawski, Robert S A1 - Peralta, Carmen A A1 - Psaty, Bruce M A1 - Harris, Tamara B A1 - Satterfield, Suzanne A1 - Shiroma, Eric J A1 - Newman, Anne B A1 - Odden, Michelle C KW - Aged KW - Aging KW - Blood Pressure KW - Blood Pressure Determination KW - Body Composition KW - California KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Hypertension KW - Incidence KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Office Visits KW - Prognosis KW - Retrospective Studies KW - Risk Factors KW - Stroke KW - Survival Rate AB -

BACKGROUND: 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.

VL - 30 IS - 2 ER - TY - JOUR T1 - Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts. JF - J Intern Med Y1 - 2018 A1 - Segna, D A1 - Bauer, D C A1 - Feller, M A1 - Schneider, C A1 - Fink, H A A1 - Aubert, C E A1 - Collet, T-H A1 - da Costa, B R A1 - Fischer, K A1 - Peeters, R P A1 - Cappola, A R A1 - Blum, M R A1 - van Dorland, H A A1 - Robbins, J A1 - Naylor, K A1 - Eastell, R A1 - Uitterlinden, A G A1 - Rivadeneira Ramirez, F A1 - Gogakos, A A1 - Gussekloo, J A1 - Williams, G R A1 - Schwartz, A A1 - Cauley, J A A1 - Aujesky, D A A1 - Bischoff-Ferrari, H A A1 - Rodondi, N KW - Aged KW - Asymptomatic Diseases KW - Bone Density KW - Female KW - Fractures, Bone KW - Humans KW - Hyperthyroidism KW - Hypothyroidism KW - Male KW - Risk Factors AB -

BACKGROUND: 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.

VL - 283 IS - 1 ER - TY - JOUR T1 - Association of Alcohol Consumption After Development of Heart Failure With Survival Among Older Adults in the Cardiovascular Health Study. JF - JAMA Netw Open Y1 - 2018 A1 - Sadhu, Justin S A1 - Novak, Eric A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R A1 - Psaty, Bruce M A1 - Stein, Phyllis K A1 - Brown, David L AB -

Importance: 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.

VL - 1 IS - 8 ER - TY - JOUR T1 - Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction. JF - JAMA Cardiol Y1 - 2018 A1 - de Boer, Rudolf A A1 - Nayor, Matthew A1 - deFilippi, Christopher R A1 - Enserro, Danielle A1 - Bhambhani, Vijeta A1 - Kizer, Jorge R A1 - Blaha, Michael J A1 - Brouwers, Frank P A1 - Cushman, Mary A1 - Lima, João A C A1 - Bahrami, Hossein A1 - van der Harst, Pim A1 - Wang, Thomas J A1 - Gansevoort, Ron T A1 - Fox, Caroline S A1 - Gaggin, Hanna K A1 - Kop, Willem J A1 - Liu, Kiang A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Lee, Douglas S A1 - Hillege, Hans L A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Chan, Cheeling A1 - Allison, Matthew A1 - Gardin, Julius M A1 - Januzzi, James L A1 - Shah, Sanjiv J A1 - Levy, Daniel A1 - Herrington, David M A1 - Larson, Martin G A1 - van Gilst, Wiek H A1 - Gottdiener, John S A1 - Bertoni, Alain G A1 - Ho, Jennifer E AB -

Importance: 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.

ER - TY - JOUR T1 - The Association of Obesity and Cardiometabolic Traits With Incident HFpEF and HFrEF. JF - JACC Heart Fail Y1 - 2018 A1 - Savji, Nazir A1 - Meijers, Wouter C A1 - Bartz, Traci M A1 - Bhambhani, Vijeta A1 - Cushman, Mary A1 - Nayor, Matthew A1 - Kizer, Jorge R A1 - Sarma, Amy A1 - Blaha, Michael J A1 - Gansevoort, Ron T A1 - Gardin, Julius M A1 - Hillege, Hans L A1 - Ji, Fei A1 - Kop, Willem J A1 - Lau, Emily S A1 - Lee, Douglas S A1 - Sadreyev, Ruslan A1 - van Gilst, Wiek H A1 - Wang, Thomas J A1 - Zanni, Markella V A1 - Vasan, Ramachandran S A1 - Allen, Norrina B A1 - Psaty, Bruce M A1 - van der Harst, Pim A1 - Levy, Daniel A1 - Larson, Martin A1 - Shah, Sanjiv J A1 - de Boer, Rudolf A A1 - Gottdiener, John S A1 - Ho, Jennifer E AB -

OBJECTIVES: 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.

VL - 6 IS - 8 ER - TY - JOUR T1 - Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). JF - Stroke Y1 - 2018 A1 - Kamel, Hooman A1 - Bartz, Traci M A1 - Elkind, Mitchell S V A1 - Okin, Peter M A1 - Thacker, Evan L A1 - Patton, Kristen K A1 - Stein, Phyllis K A1 - deFilippi, Christopher R A1 - Gottesman, Rebecca F A1 - Heckbert, Susan R A1 - Kronmal, Richard A A1 - Soliman, Elsayed Z A1 - Longstreth, W T AB -

BACKGROUND 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.

VL - 49 IS - 4 ER - TY - JOUR T1 - Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2018 A1 - Lemaitre, Rozenn N A1 - McKnight, Barbara A1 - Sotoodehnia, Nona A1 - Fretts, Amanda M A1 - Qureshi, Waqas T A1 - Song, Xiaoling A1 - King, Irena B A1 - Sitlani, Colleen M A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Mozaffarian, Dariush AB -

Background 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.

VL - 7 IS - 21 ER - TY - JOUR T1 - Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. JF - Circ Genom Precis Med Y1 - 2018 A1 - Lin, Honghuang A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Bihlmeyer, Nathan A A1 - Warren, Helen R A1 - Brody, Jennifer A A1 - Radmanesh, Farid A1 - Hall, Leanne A1 - Grarup, Niels A1 - Müller-Nurasyid, Martina A1 - Boutin, Thibaud A1 - Verweij, Niek A1 - Lin, Henry J A1 - Li-Gao, Ruifang A1 - van den Berg, Marten E A1 - Marten, Jonathan A1 - Weiss, Stefan A1 - Prins, Bram P A1 - Haessler, Jeffrey A1 - Lyytikäinen, Leo-Pekka A1 - Mei, Hao A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Li, Man A1 - Alonso, Alvaro A1 - Soliman, Elsayed Z A1 - Connell, John M A1 - Huang, Paul L A1 - Weng, Lu-Chen A1 - Jameson, Heather S A1 - Hucker, William A1 - Hanley, Alan A1 - Tucker, Nathan R A1 - Chen, Yii-Der Ida A1 - Bis, Joshua C A1 - Rice, Kenneth M A1 - Sitlani, Colleen M A1 - Kors, Jan A A1 - Xie, Zhijun A1 - Wen, Chengping A1 - Magnani, Jared W A1 - Nelson, Christopher P A1 - Kanters, Jørgen K A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Bork-Jensen, Jette A1 - Pedersen, Oluf A1 - Linneberg, Allan A1 - Rudan, Igor A1 - de Boer, Rudolf A A1 - van der Meer, Peter A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Sotoodehnia, Nona A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Trompet, Stella A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Eijgelsheim, Mark A1 - Padmanabhan, Sandosh A1 - Smith, Blair H A1 - Völzke, Henry A1 - Felix, Stephan B A1 - Homuth, Georg A1 - Völker, Uwe A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Bots, Michiel L A1 - Perez, Marco A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - Arking, Dan E A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Benjamin, Emelia J A1 - Rosand, Jonathan A1 - Samani, Nilesh J A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Polasek, Ozren A1 - van der Harst, Pim A1 - Heckbert, Susan R A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Hayward, Caroline A1 - Dörr, Marcus A1 - Jamshidi, Yalda A1 - Asselbergs, Folkert W A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Wilson, James G A1 - Ellinor, Patrick T A1 - Lubitz, Steven A A1 - Isaacs, Aaron AB -

BACKGROUND: 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.

VL - 11 IS - 5 ER - TY - JOUR T1 - Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. JF - Circ Genom Precis Med Y1 - 2018 A1 - Macri, Vincenzo A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Hucker, William J A1 - Yin, Xiaoyan A1 - Lin, Honghuang A1 - Mills, Robert W A1 - Sinner, Moritz F A1 - Lubitz, Steven A A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Alonso, Alvaro A1 - Li, Ning A1 - Fedorov, Vadim V A1 - Janssen, Paul M A1 - Bis, Joshua C A1 - Heckbert, Susan R A1 - Dolmatova, Elena V A1 - Lumley, Thomas A1 - Sitlani, Colleen M A1 - Cupples, L Adrienne A1 - Pulit, Sara L A1 - Newton-Cheh, Christopher A1 - Barnard, John A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Chung, Mina K A1 - Vlahakes, Gus J A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Margulies, Kenneth B A1 - Morley, Michael P A1 - Cappola, Thomas P A1 - Benjamin, Emelia J A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Jackson, Rebecca D A1 - Magnani, Jared W A1 - Herndon, Caroline N A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Milan, David J A1 - Boerwinkle, Eric A1 - Mohler, Peter J A1 - Sotoodehnia, Nona A1 - Ellinor, Patrick T AB -

BACKGROUND: 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.

VL - 11 IS - 5 ER - TY - JOUR T1 - Comparison of 2 Treatment Models: Precision Medicine and Preventive Medicine. JF - JAMA Y1 - 2018 A1 - Psaty, Bruce M A1 - Dekkers, Olaf M A1 - Cooper, Richard S KW - Humans KW - Precision Medicine KW - Preventive Medicine VL - 320 IS - 8 ER - TY - JOUR T1 - A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. JF - Eur Heart J Y1 - 2018 A1 - Ashar, Foram N A1 - Mitchell, Rebecca N A1 - Albert, Christine M A1 - Newton-Cheh, Christopher A1 - Brody, Jennifer A A1 - Müller-Nurasyid, Martina A1 - Moes, Anna A1 - Meitinger, Thomas A1 - Mak, Angel A1 - Huikuri, Heikki A1 - Junttila, M Juhani A1 - Goyette, Philippe A1 - Pulit, Sara L A1 - Pazoki, Raha A1 - Tanck, Michael W A1 - Blom, Marieke T A1 - Zhao, XiaoQing A1 - Havulinna, Aki S A1 - Jabbari, Reza A1 - Glinge, Charlotte A1 - Tragante, Vinicius A1 - Escher, Stefan A A1 - Chakravarti, Aravinda A1 - Ehret, Georg A1 - Coresh, Josef A1 - Li, Man A1 - Prineas, Ronald J A1 - Franco, Oscar H A1 - Kwok, Pui-Yan A1 - Lumley, Thomas A1 - Dumas, Florence A1 - McKnight, Barbara A1 - Rotter, Jerome I A1 - Lemaitre, Rozenn N A1 - Heckbert, Susan R A1 - O'Donnell, Christopher J A1 - Hwang, Shih-Jen A1 - Tardif, Jean-Claude A1 - VanDenburgh, Martin A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Stricker, Bruno H C A1 - de Bakker, Paul I W A1 - Franks, Paul W A1 - Jansson, Jan-Håkan A1 - Asselbergs, Folkert W A1 - Halushka, Marc K A1 - Maleszewski, Joseph J A1 - Tfelt-Hansen, Jacob A1 - Engstrøm, Thomas A1 - Salomaa, Veikko A1 - Virmani, Renu A1 - Kolodgie, Frank A1 - Wilde, Arthur A M A1 - Tan, Hanno L A1 - Bezzina, Connie R A1 - Eijgelsheim, Mark A1 - Rioux, John D A1 - Jouven, Xavier A1 - Kääb, Stefan A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

Aims: 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.

ER - TY - JOUR T1 - {Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies JF - Clin Chem Y1 - 2018 A1 - Huang, T. A1 - Ding, M. A1 - Bergholdt, H. K. M. A1 - Wang, T. A1 - Heianza, Y. A1 - Sun, D. A1 - Frazier-Wood, A. C. A1 - Aslibekyan, S. A1 - North, K. E. A1 - Voortman, T. A1 - Graff, M. A1 - Smith, C. E. A1 - Lai, C. Q. A1 - Varbo, A. A1 - Lemaitre, R. N. A1 - de Jonge, M. E. A. L. A1 - Fumeron, F. A1 - Corella, D. A1 - Wang, C. A. A1 - Tj?nneland, A. A1 - Overvad, K. A1 - S?rensen, T. I. A. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - K?h?nen, M. A1 - Renstr?m, F. A1 - Psaty, B. M. A1 - Siscovick, D. S. A1 - Barroso, I. A1 - Johansson, I. A1 - Hernandez, D. A1 - Ferrucci, L. A1 - Bandinelli, S. A1 - Linneberg, A. A1 - Zillikens, M. C. A1 - Sandholt, C. H. A1 - Pedersen, O. A1 - Hansen, T. A1 - Schulz, C. A. A1 - Sonestedt, E. A1 - Orho-Melander, M. A1 - Chen, T. A. A1 - Rotter, J. I. A1 - Allison, M. A. A1 - Rich, S. S. A1 - Sorl?, J. V. A1 - Coltell, O. A1 - Pennell, C. E. A1 - Eastwood, P. A1 - Hofman, A. A1 - Uitterlinden, A. G. A1 - van Rooij, F. J. A. A1 - Chu, A. Y. A1 - Rose, L. M. A1 - Ridker, P. M. A1 - Viikari, J. A1 - Raitakari, O. A1 - Lehtim?ki, T. A1 - Mikkil?, V. A1 - Willett, W. C. A1 - Wang, Y. A1 - Tucker, K. L. A1 - Ordovas, J. M. A1 - Kilpel?inen, T. O. A1 - Province, M. A. A1 - Franks, P. W. A1 - Arnett, D. K. A1 - Tanaka, T. A1 - Toft, U. A1 - Ericson, U. A1 - Franco, O. H. A1 - Mozaffarian, D. A1 - Hu, F. B. A1 - Chasman, D. I. A1 - Nordestgaard, B. G. A1 - Ellervik, C. A1 - Qi, L. AB - Associations 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. VL - 64 ER - TY - JOUR T1 - Discovery, 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. JF - Hum Mol Genet Y1 - 2018 A1 - Kocarnik, Jonathan M A1 - Richard, Melissa A1 - Graff, Misa A1 - Haessler, Jeffrey A1 - Bien, Stephanie A1 - Carlson, Chris A1 - Carty, Cara L A1 - Reiner, Alexander P A1 - Avery, Christy L A1 - Ballantyne, Christie M A1 - LaCroix, Andrea Z A1 - Assimes, Themistocles L A1 - Barbalic, Maja A1 - Pankratz, Nathan A1 - Tang, Weihong A1 - Tao, Ran A1 - Chen, Dongquan A1 - Talavera, Gregory A A1 - Daviglus, Martha L A1 - Chirinos-Medina, Diana A A1 - Pereira, Rocio A1 - Nishimura, Katie A1 - Bůzková, Petra A1 - Best, Lyle G A1 - Ambite, Jose Luis A1 - Cheng, Iona A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Fornage, Myriam A1 - Heiss, Gerardo A1 - North, Kari E A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Le Marchand, Loïc A1 - Kooperberg, Charles AB -

C-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.

VL - 27 IS - 16 ER - TY - JOUR T1 - DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis. JF - Blood Y1 - 2018 A1 - Ward-Caviness, Cavin K A1 - Huffman, Jennifer E A1 - Evertt, Karl A1 - Germain, Marine A1 - van Dongen, Jenny A1 - Hill, W David A1 - Jhun, Min A A1 - Brody, Jennifer A A1 - Ghanbari, Mohsen A1 - Du, Lei A1 - Roetker, Nicholas S A1 - de Vries, Paul S A1 - Waldenberger, Melanie A1 - Gieger, Christian A1 - Wolf, Petra A1 - Prokisch, Holger A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Levy, Daniel A1 - Liu, Chunyu A1 - Truong, Vinh A1 - Wells, Philip S A1 - Trégouët, David-Alexandre A1 - Tang, Weihong A1 - Morrison, Alanna C A1 - Boerwinkle, Eric A1 - Wiggins, Kerri L A1 - McKnight, Barbara A1 - Guo, Xiuqing A1 - Psaty, Bruce M A1 - Sotoodenia, Nona A1 - Boomsa, Dorret I A1 - Willemsen, Gonneke A1 - Ligthart, Lannie A1 - Deary, Ian J A1 - Zhao, Wei A1 - Ware, Erin B A1 - Kardia, Sharon L R A1 - van Meurs, Joyce B J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Eriksson, Per A1 - Franco-Cereceda, Anders A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Gagnon, France A1 - Morange, Pierre-Emmanuel A1 - de Geus, Eco J C A1 - Starr, John M A1 - Smith, Jennifer A A1 - Dehghan, Abbas A1 - Björck, Hanna M A1 - Smith, Nicholas L A1 - Peters, Annette AB -

Many 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.

ER - TY - JOUR T1 - Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies. JF - Eur Heart J Y1 - 2018 A1 - Pennells, Lisa A1 - Kaptoge, Stephen A1 - Wood, Angela A1 - Sweeting, Mike A1 - Zhao, Xiaohui A1 - White, Ian A1 - Burgess, Stephen A1 - Willeit, Peter A1 - Bolton, Thomas A1 - Moons, Karel G M A1 - van der Schouw, Yvonne T A1 - Selmer, Randi A1 - Khaw, Kay-Tee A1 - Gudnason, Vilmundur A1 - Assmann, Gerd A1 - Amouyel, Philippe A1 - Salomaa, Veikko A1 - Kivimaki, Mika A1 - Nordestgaard, Børge G A1 - Blaha, Michael J A1 - Kuller, Lewis H A1 - Brenner, Hermann A1 - Gillum, Richard F A1 - Meisinger, Christa A1 - Ford, Ian A1 - Knuiman, Matthew W A1 - Rosengren, Annika A1 - Lawlor, Debbie A A1 - Völzke, Henry A1 - Cooper, Cyrus A1 - Marín Ibañez, Alejandro A1 - Casiglia, Edoardo A1 - Kauhanen, Jussi A1 - Cooper, Jackie A A1 - Rodriguez, Beatriz A1 - Sundström, Johan A1 - Barrett-Connor, Elizabeth A1 - Dankner, Rachel A1 - Nietert, Paul J A1 - Davidson, Karina W A1 - Wallace, Robert B A1 - Blazer, Dan G A1 - Björkelund, Cecilia A1 - Donfrancesco, Chiara A1 - Krumholz, Harlan M A1 - Nissinen, Aulikki A1 - Davis, Barry R A1 - Coady, Sean A1 - Whincup, Peter H A1 - Jørgensen, Torben A1 - Ducimetiere, Pierre A1 - Trevisan, Maurizio A1 - Engström, Gunnar A1 - Crespo, Carlos J A1 - Meade, Tom W A1 - Visser, Marjolein A1 - Kromhout, Daan A1 - Kiechl, Stefan A1 - Daimon, Makoto A1 - Price, Jackie F A1 - Gómez de la Cámara, Agustin A1 - Wouter Jukema, J A1 - Lamarche, Benoît A1 - Onat, Altan A1 - Simons, Leon A A1 - Kavousi, Maryam A1 - Ben-Shlomo, Yoav A1 - Gallacher, John A1 - Dekker, Jacqueline M A1 - Arima, Hisatomi A1 - Shara, Nawar A1 - Tipping, Robert W A1 - Roussel, Ronan A1 - Brunner, Eric J A1 - Koenig, Wolfgang A1 - Sakurai, Masaru A1 - Pavlovic, Jelena A1 - Gansevoort, Ron T A1 - Nagel, Dorothea A1 - Goldbourt, Uri A1 - Barr, Elizabeth L M A1 - Palmieri, Luigi A1 - Njølstad, Inger A1 - Sato, Shinichi A1 - Monique Verschuren, W M A1 - Varghese, Cherian V A1 - Graham, Ian A1 - Onuma, Oyere A1 - Greenland, Philip A1 - Woodward, Mark A1 - Ezzati, Majid A1 - Psaty, Bruce M A1 - Sattar, Naveed A1 - Jackson, Rod A1 - Ridker, Paul M A1 - Cook, Nancy R A1 - D'Agostino, Ralph B A1 - Thompson, Simon G A1 - Danesh, John A1 - Di Angelantonio, Emanuele AB -

Aims: 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.

ER - TY - JOUR T1 - Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. JF - Stroke Y1 - 2018 A1 - Jian, Xueqiu A1 - Satizabal, Claudia L A1 - Smith, Albert V A1 - Wittfeld, Katharina A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Hsu, Fang-Chi A1 - Nho, Kwangsik A1 - Hofer, Edith A1 - Hagenaars, Saskia P A1 - Nyquist, Paul A A1 - Mishra, Aniket A1 - Adams, Hieab H H A1 - Li, Shuo A1 - Teumer, Alexander A1 - Zhao, Wei A1 - Freedman, Barry I A1 - Saba, Yasaman A1 - Yanek, Lisa R A1 - Chauhan, Ganesh A1 - van Buchem, Mark A A1 - Cushman, Mary A1 - Royle, Natalie A A1 - Bryan, R Nick A1 - Niessen, Wiro J A1 - Windham, Beverly G A1 - DeStefano, Anita L A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Palmer, Nicholette D A1 - Lewis, Cora E A1 - Eiriksdottir, Gudny A1 - Maillard, Pauline A1 - Mathias, Rasika A A1 - Homuth, Georg A1 - Valdés-Hernández, Maria Del C A1 - Divers, Jasmin A1 - Beiser, Alexa S A1 - Langner, Sönke A1 - Rice, Kenneth M A1 - Bastin, Mark E A1 - Yang, Qiong A1 - Maldjian, Joseph A A1 - Starr, John M A1 - Sidney, Stephen A1 - Risacher, Shannon L A1 - Uitterlinden, André G A1 - Gudnason, Vilmundur G A1 - Nauck, Matthias A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Boerwinkle, Eric A1 - van Duijn, Cornelia M A1 - Mazoyer, Bernard A1 - von Sarnowski, Bettina A1 - Gottesman, Rebecca F A1 - Levy, Daniel A1 - Sigurdsson, Sigurdur A1 - Vernooij, Meike W A1 - Turner, Stephen T A1 - Schmidt, Reinhold A1 - Wardlaw, Joanna M A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - DeCarli, Charles S A1 - Saykin, Andrew J A1 - Bowden, Donald W A1 - Becker, Diane M A1 - Deary, Ian J A1 - Schmidt, Helena A1 - Kardia, Sharon L R A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Grabe, Hans J A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Fornage, Myriam AB -

BACKGROUND 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.

ER - TY - JOUR T1 - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. JF - Genome Biol Y1 - 2018 A1 - Prins, Bram P A1 - Mead, Timothy J A1 - Brody, Jennifer A A1 - Sveinbjornsson, Gardar A1 - Ntalla, Ioanna A1 - Bihlmeyer, Nathan A A1 - van den Berg, Marten A1 - Bork-Jensen, Jette A1 - Cappellani, Stefania A1 - Van Duijvenboden, Stefan A1 - Klena, Nikolai T A1 - Gabriel, George C A1 - Liu, Xiaoqin A1 - Gulec, Cagri A1 - Grarup, Niels A1 - Haessler, Jeffrey A1 - Hall, Leanne M A1 - Iorio, Annamaria A1 - Isaacs, Aaron A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Liu, Ching-Ti A1 - Lyytikäinen, Leo-Pekka A1 - Marten, Jonathan A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Orini, Michele A1 - Padmanabhan, Sandosh A1 - Radmanesh, Farid A1 - Ramirez, Julia A1 - Robino, Antonietta A1 - Schwartz, Molly A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Verweij, Niek A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Alonso, Alvaro A1 - Arnar, David O A1 - Bots, Michiel L A1 - de Boer, Rudolf A A1 - Dominiczak, Anna F A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Guo, Xiuqing A1 - Felix, Stephan B A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Jukema, J W A1 - Kähönen, Mika A1 - Kors, Jan A A1 - Lambiase, Pier D A1 - Launer, Lenore J A1 - Li, Man A1 - Linneberg, Allan A1 - Nelson, Christopher P A1 - Pedersen, Oluf A1 - Perez, Marco A1 - Peters, Annette A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Tim D A1 - Strauch, Konstantin A1 - Thorsteinsdottir, Unnur A1 - Tinker, Andrew A1 - Trompet, Stella A1 - Uitterlinden, Andre A1 - Vaartjes, Ilonca A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wilson, James G A1 - Xie, Zhijun A1 - Asselbergs, Folkert W A1 - Dörr, Marcus A1 - van Duijn, Cornelia M A1 - Gasparini, Paolo A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Kanters, Jørgen K A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Lin, Henry J A1 - Lubitz, Steven A A1 - Mook-Kanamori, Dennis O A1 - Conti, Francesco J A1 - Newton-Cheh, Christopher H A1 - Rosand, Jonathan A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Smith, Blair H A1 - Holm, Hilma A1 - Stricker, Bruno H A1 - Ulivi, Sheila A1 - Sotoodehnia, Nona A1 - Apte, Suneel S A1 - van der Harst, Pim A1 - Stefansson, Kari A1 - Munroe, Patricia B A1 - Arking, Dan E A1 - Lo, Cecilia W A1 - Jamshidi, Yalda AB -

BACKGROUND: 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.

VL - 19 IS - 1 ER - TY - JOUR T1 - ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. JF - Circ Genom Precis Med Y1 - 2018 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Smith, Albert Vernon A1 - Warren, Helen R A1 - Lin, Honghuang A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Marten, Jonathan A1 - Radmanesh, Farid A1 - Hall, Leanne M A1 - Grarup, Niels A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Huffman, Jennifer E A1 - Verweij, Niek A1 - Guo, Xiuqing A1 - Yao, Jie A1 - Li-Gao, Ruifang A1 - van den Berg, Marten A1 - Weiss, Stefan A1 - Prins, Bram P A1 - van Setten, Jessica A1 - Haessler, Jeffrey A1 - Lyytikäinen, Leo-Pekka A1 - Li, Man A1 - Alonso, Alvaro A1 - Soliman, Elsayed Z A1 - Bis, Joshua C A1 - Austin, Tom A1 - Chen, Yii-Der Ida A1 - Psaty, Bruce M A1 - Harrris, Tamara B A1 - Launer, Lenore J A1 - Padmanabhan, Sandosh A1 - Dominiczak, Anna A1 - Huang, Paul L A1 - Xie, Zhijun A1 - Ellinor, Patrick T A1 - Kors, Jan A A1 - Campbell, Archie A1 - Murray, Alison D A1 - Nelson, Christopher P A1 - Tobin, Martin D A1 - Bork-Jensen, Jette A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Linneberg, Allan A1 - Sinner, Moritz F A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Kolcic, Ivana A1 - Rudan, Igor A1 - de Boer, Rudolf A A1 - van der Meer, Peter A1 - Lin, Henry J A1 - Taylor, Kent D A1 - de Mutsert, Renée A1 - Trompet, Stella A1 - Jukema, J Wouter A1 - Maan, Arie C A1 - Stricker, Bruno H C A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Völker, Uwe A1 - Homuth, Georg A1 - Völzke, Henry A1 - Felix, Stephan B A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Bots, Michiel L A1 - Perez, Marco A1 - Raitakari, Olli T A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Gudnason, Vilmundur A1 - Munroe, Patricia B A1 - Lubitz, Steven A A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher H A1 - Hayward, Caroline A1 - Rosand, Jonathan A1 - Samani, Nilesh J A1 - Kanters, Jørgen K A1 - Wilson, James G A1 - Kääb, Stefan A1 - Polasek, Ozren A1 - van der Harst, Pim A1 - Heckbert, Susan R A1 - Rotter, Jerome I A1 - Mook-Kanamori, Dennis O A1 - Eijgelsheim, Mark A1 - Dörr, Marcus A1 - Jamshidi, Yalda A1 - Asselbergs, Folkert W A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

BACKGROUND: 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.

VL - 11 IS - 1 ER - TY - JOUR T1 - FastSKAT: Sequence kernel association tests for very large sets of markers. JF - Genet Epidemiol Y1 - 2018 A1 - Lumley, Thomas A1 - Brody, Jennifer A1 - Peloso, Gina A1 - Morrison, Alanna A1 - Rice, Kenneth KW - Algorithms KW - Chromosomes, Human KW - Genetic Association Studies KW - Genetic Markers KW - Histones KW - Humans KW - Sequence Analysis, DNA KW - Statistics as Topic KW - Time Factors AB -

The 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.

VL - 42 IS - 6 ER - TY - JOUR T1 - Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. JF - Nat Genet Y1 - 2018 A1 - Evangelou, Evangelos A1 - Warren, Helen R A1 - Mosen-Ansorena, David A1 - Mifsud, Borbala A1 - Pazoki, Raha A1 - Gao, He A1 - Ntritsos, Georgios A1 - Dimou, Niki A1 - Cabrera, Claudia P A1 - Karaman, Ibrahim A1 - Ng, Fu Liang A1 - Evangelou, Marina A1 - Witkowska, Katarzyna A1 - Tzanis, Evan A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - Velez Edwards, Digna R A1 - Sun, Yan V A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Kovesdy, Csaba P A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Milani, Lili A1 - Almgren, Peter A1 - Boutin, Thibaud A1 - Debette, Stephanie A1 - Ding, Jun A1 - Giulianini, Franco A1 - Holliday, Elizabeth G A1 - Jackson, Anne U A1 - Li-Gao, Ruifang A1 - Lin, Wei-Yu A1 - Luan, Jian'an A1 - Mangino, Massimo A1 - Oldmeadow, Christopher A1 - Prins, Bram Peter A1 - Qian, Yong A1 - Sargurupremraj, Muralidharan A1 - Shah, Nabi A1 - Surendran, Praveen A1 - Thériault, Sébastien A1 - Verweij, Niek A1 - Willems, Sara M A1 - Zhao, Jing-Hua A1 - Amouyel, Philippe A1 - Connell, John A1 - de Mutsert, Renée A1 - Doney, Alex S F A1 - Farrall, Martin A1 - Menni, Cristina A1 - Morris, Andrew D A1 - Noordam, Raymond A1 - Paré, Guillaume A1 - Poulter, Neil R A1 - Shields, Denis C A1 - Stanton, Alice A1 - Thom, Simon A1 - Abecasis, Goncalo A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ayers, Kristin L A1 - Barbieri, Caterina M A1 - Batini, Chiara A1 - Bis, Joshua C A1 - Blake, Tineka A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brumat, Marco A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chauhan, Ganesh A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Cordell, Heather J A1 - Davies, Gail A1 - Borst, Martin H de A1 - Geus, Eco J de A1 - Deary, Ian J A1 - Deelen, Joris A1 - del Greco M, Fabiola A1 - Demirkale, Cumhur Yusuf A1 - Dörr, Marcus A1 - Ehret, Georg B A1 - Elosua, Roberto A1 - Enroth, Stefan A1 - Erzurumluoglu, A Mesut A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Franco, Oscar H A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gow, Alan J A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Harris, Sarah E A1 - Hartman, Catharina A A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Ingelsson, Erik A1 - James, Alan A1 - Jansen, Rick A1 - Jarvelin, Marjo-Riitta A1 - Joehanes, Roby A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Joshi, Peter K A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Keavney, Bernard D A1 - Khaw, Kay-Tee A1 - Knekt, Paul A1 - Knight, Joanne A1 - Kolcic, Ivana A1 - Kooner, Jaspal S A1 - Koskinen, Seppo A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Laan, Maris A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lopez, Lorna M A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Mamasoula, Chrysovalanto A1 - Marrugat, Jaume A1 - Marten, Jonathan A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nalls, Mike A A1 - Nandakumar, Priyanka A1 - Nelson, Christopher P A1 - Niiranen, Teemu A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - O'Reilly, Paul F A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Palotie, Aarno A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Nguyen, Quang Tri A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rettig, Rainer A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Ried, Janina S A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia F A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Shrine, Nick A1 - Siscovick, David A1 - Smith, Albert V A1 - Snieder, Harold A1 - Sõber, Siim A1 - Sorice, Rossella A1 - Starr, John M A1 - Stott, David J A1 - Strachan, David P A1 - Strawbridge, Rona J A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Tobin, Martin D A1 - Tomaszewski, Maciej A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Trompet, Stella A1 - Tuomilehto, Jaakko A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Vaez, Ahmad A1 - van der Most, Peter J A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Verwoert, Germaine C A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Yao, Jie A1 - Zemunik, Tatijana A1 - Zhang, Weihua A1 - Attia, John R A1 - Butterworth, Adam S A1 - Chasman, Daniel I A1 - Conen, David A1 - Cucca, Francesco A1 - Danesh, John A1 - Hayward, Caroline A1 - Howson, Joanna M M A1 - Laakso, Markku A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Melander, Olle A1 - Mook-Kanamori, Dennis O A1 - Palmer, Colin N A A1 - Risch, Lorenz A1 - Scott, Robert A A1 - Scott, Rodney J A1 - Sever, Peter A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Zeggini, Eleftheria A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Brown, Morris J A1 - Metspalu, Andres A1 - Hung, Adriana M A1 - O'Donnell, Christopher J A1 - Edwards, Todd L A1 - Psaty, Bruce M A1 - Tzoulaki, Ioanna A1 - Barnes, Michael R A1 - Wain, Louise V A1 - Elliott, Paul A1 - Caulfield, Mark J AB -

High 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.

VL - 50 IS - 10 ER - TY - JOUR T1 - Genetic Variants Associated with Circulating Fibroblast Growth Factor 23. JF - J Am Soc Nephrol Y1 - 2018 A1 - Robinson-Cohen, Cassianne A1 - Bartz, Traci M A1 - Lai, Dongbing A1 - Ikizler, T Alp A1 - Peacock, Munro A1 - Imel, Erik A A1 - Michos, Erin D A1 - Foroud, Tatiana M A1 - Åkesson, Kristina A1 - Taylor, Kent D A1 - Malmgren, Linnea A1 - Matsushita, Kunihiro A1 - Nethander, Maria A1 - Eriksson, Joel A1 - Ohlsson, Claes A1 - Mellström, Daniel A1 - Wolf, Myles A1 - Ljunggren, Osten A1 - McGuigan, Fiona A1 - Rotter, Jerome I A1 - Karlsson, Magnus A1 - Econs, Michael J A1 - Ix, Joachim H A1 - Lutsey, Pamela L A1 - Psaty, Bruce M A1 - de Boer, Ian H A1 - Kestenbaum, Bryan R AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. JF - Dement Geriatr Cogn Disord Y1 - 2018 A1 - Blue, Elizabeth E A1 - Bis, Joshua C A1 - Dorschner, Michael O A1 - Tsuang, Debby W A1 - Barral, Sandra M A1 - Beecham, Gary A1 - Below, Jennifer E A1 - Bush, William S A1 - Butkiewicz, Mariusz A1 - Cruchaga, Carlos A1 - DeStefano, Anita A1 - Farrer, Lindsay A A1 - Goate, Alison A1 - Haines, Jonathan A1 - Jaworski, Jim A1 - Jun, Gyungah A1 - Kunkle, Brian A1 - Kuzma, Amanda A1 - Lee, Jenny J A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Martin, Eden A1 - Naj, Adam A1 - Nato, Alejandro Q A1 - Navas, Patrick A1 - Nguyen, Hiep A1 - Reitz, Christiane A1 - Reyes, Dolly A1 - Salerno, William A1 - Schellenberg, Gerard D A1 - Seshadri, Sudha A1 - Sohi, Harkirat A1 - Thornton, Timothy A A1 - Valadares, Otto A1 - van Duijn, Cornelia A1 - Vardarajan, Badri N A1 - Wang, Li-San A1 - Boerwinkle, Eric A1 - Dupuis, Josée A1 - Pericak-Vance, Margaret A A1 - Mayeux, Richard A1 - Wijsman, Ellen M AB -

BACKGROUND/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.

VL - 45 IS - 1-2 ER - TY - JOUR T1 - Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease. JF - Alzheimers Dement (Amst) Y1 - 2018 A1 - Peloso, Gina M A1 - van der Lee, Sven J A1 - DeStefano, Anita L A1 - Seshardi, Sudha AB -

Introduction: 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.

VL - 10 ER - TY - JOUR T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. JF - Am J Hum Genet Y1 - 2018 A1 - Ligthart, Symen A1 - Vaez, Ahmad A1 - Võsa, Urmo A1 - Stathopoulou, Maria G A1 - de Vries, Paul S A1 - Prins, Bram P A1 - van der Most, Peter J A1 - Tanaka, Toshiko A1 - Naderi, Elnaz A1 - Rose, Lynda M A1 - Wu, Ying A1 - Karlsson, Robert A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Pool, Rene A1 - Zhu, Gu A1 - Mace, Aurelien A1 - Sidore, Carlo A1 - Trompet, Stella A1 - Mangino, Massimo A1 - Sabater-Lleal, Maria A1 - Kemp, John P A1 - Abbasi, Ali A1 - Kacprowski, Tim A1 - Verweij, Niek A1 - Smith, Albert V A1 - Huang, Tao A1 - Marzi, Carola A1 - Feitosa, Mary F A1 - Lohman, Kurt K A1 - Kleber, Marcus E A1 - Milaneschi, Yuri A1 - Mueller, Christian A1 - Huq, Mahmudul A1 - Vlachopoulou, Efthymia A1 - Lyytikäinen, Leo-Pekka A1 - Oldmeadow, Christopher A1 - Deelen, Joris A1 - Perola, Markus A1 - Zhao, Jing Hua A1 - Feenstra, Bjarke A1 - Amini, Marzyeh A1 - Lahti, Jari A1 - Schraut, Katharina E A1 - Fornage, Myriam A1 - Suktitipat, Bhoom A1 - Chen, Wei-Min A1 - Li, Xiaohui A1 - Nutile, Teresa A1 - Malerba, Giovanni A1 - Luan, Jian'an A1 - Bak, Tom A1 - Schork, Nicholas A1 - del Greco M, Fabiola A1 - Thiering, Elisabeth A1 - Mahajan, Anubha A1 - Marioni, Riccardo E A1 - Mihailov, Evelin A1 - Eriksson, Joel A1 - Ozel, Ayse Bilge A1 - Zhang, Weihua A1 - Nethander, Maria A1 - Cheng, Yu-Ching A1 - Aslibekyan, Stella A1 - Ang, Wei A1 - Gandin, Ilaria A1 - Yengo, Loic A1 - Portas, Laura A1 - Kooperberg, Charles A1 - Hofer, Edith A1 - Rajan, Kumar B A1 - Schurmann, Claudia A1 - den Hollander, Wouter A1 - Ahluwalia, Tarunveer S A1 - Zhao, Jing A1 - Draisma, Harmen H M A1 - Ford, Ian A1 - Timpson, Nicholas A1 - Teumer, Alexander A1 - Huang, Hongyan A1 - Wahl, Simone A1 - Liu, Yongmei A1 - Huang, Jie A1 - Uh, Hae-Won A1 - Geller, Frank A1 - Joshi, Peter K A1 - Yanek, Lisa R A1 - Trabetti, Elisabetta A1 - Lehne, Benjamin A1 - Vozzi, Diego A1 - Verbanck, Marie A1 - Biino, Ginevra A1 - Saba, Yasaman A1 - Meulenbelt, Ingrid A1 - O'Connell, Jeff R A1 - Laakso, Markku A1 - Giulianini, Franco A1 - Magnusson, Patrik K E A1 - Ballantyne, Christie M A1 - Hottenga, Jouke Jan A1 - Montgomery, Grant W A1 - Rivadineira, Fernando A1 - Rueedi, Rico A1 - Steri, Maristella A1 - Herzig, Karl-Heinz A1 - Stott, David J A1 - Menni, Cristina A1 - Frånberg, Mattias A1 - St Pourcain, Beate A1 - Felix, Stephan B A1 - Pers, Tune H A1 - Bakker, Stephan J L A1 - Kraft, Peter A1 - Peters, Annette A1 - Vaidya, Dhananjay A1 - Delgado, Graciela A1 - Smit, Johannes H A1 - Großmann, Vera A1 - Sinisalo, Juha A1 - Seppälä, Ilkka A1 - Williams, Stephen R A1 - Holliday, Elizabeth G A1 - Moed, Matthijs A1 - Langenberg, Claudia A1 - Räikkönen, Katri A1 - Ding, Jingzhong A1 - Campbell, Harry A1 - Sale, Michèle M A1 - Chen, Yii-der I A1 - James, Alan L A1 - Ruggiero, Daniela A1 - Soranzo, Nicole A1 - Hartman, Catharina A A1 - Smith, Erin N A1 - Berenson, Gerald S A1 - Fuchsberger, Christian A1 - Hernandez, Dena A1 - Tiesler, Carla M T A1 - Giedraitis, Vilmantas A1 - Liewald, David A1 - Fischer, Krista A1 - Mellström, Dan A1 - Larsson, Anders A1 - Wang, Yunmei A1 - Scott, William R A1 - Lorentzon, Matthias A1 - Beilby, John A1 - Ryan, Kathleen A A1 - Pennell, Craig E A1 - Vuckovic, Dragana A1 - Balkau, Beverly A1 - Concas, Maria Pina A1 - Schmidt, Reinhold A1 - Mendes de Leon, Carlos F A1 - Bottinger, Erwin P A1 - Kloppenburg, Margreet A1 - Paternoster, Lavinia A1 - Boehnke, Michael A1 - Musk, A W A1 - Willemsen, Gonneke A1 - Evans, David M A1 - Madden, Pamela A F A1 - Kähönen, Mika A1 - Kutalik, Zoltán A1 - Zoledziewska, Magdalena A1 - Karhunen, Ville A1 - Kritchevsky, Stephen B A1 - Sattar, Naveed A1 - Lachance, Genevieve A1 - Clarke, Robert A1 - Harris, Tamara B A1 - Raitakari, Olli T A1 - Attia, John R A1 - van Heemst, Diana A1 - Kajantie, Eero A1 - Sorice, Rossella A1 - Gambaro, Giovanni A1 - Scott, Robert A A1 - Hicks, Andrew A A1 - Ferrucci, Luigi A1 - Standl, Marie A1 - Lindgren, Cecilia M A1 - Starr, John M A1 - Karlsson, Magnus A1 - Lind, Lars A1 - Li, Jun Z A1 - Chambers, John C A1 - Mori, Trevor A A1 - de Geus, Eco J C N A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Auvinen, Juha A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Waldenberger, Melanie A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Scott, Rodney J A1 - McEvoy, Mark A1 - Beekman, Marian A1 - Bombieri, Cristina A1 - Ridker, Paul M A1 - Mohlke, Karen L A1 - Pedersen, Nancy L A1 - Morrison, Alanna C A1 - Boomsma, Dorret I A1 - Whitfield, John B A1 - Strachan, David P A1 - Hofman, Albert A1 - Vollenweider, Peter A1 - Cucca, Francesco A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Spector, Tim D A1 - Hamsten, Anders A1 - Zeller, Tanja A1 - Uitterlinden, André G A1 - Nauck, Matthias A1 - Gudnason, Vilmundur A1 - Qi, Lu A1 - Grallert, Harald A1 - Borecki, Ingrid B A1 - Rotter, Jerome I A1 - März, Winfried A1 - Wild, Philipp S A1 - Lokki, Marja-Liisa A1 - Boyle, Michael A1 - Salomaa, Veikko A1 - Melbye, Mads A1 - Eriksson, Johan G A1 - Wilson, James F A1 - Penninx, Brenda W J H A1 - Becker, Diane M A1 - Worrall, Bradford B A1 - Gibson, Greg A1 - Krauss, Ronald M A1 - Ciullo, Marina A1 - Zaza, Gianluigi A1 - Wareham, Nicholas J A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Murray, Sarah S A1 - Pramstaller, Peter P A1 - Bandinelli, Stefania A1 - Heinrich, Joachim A1 - Ingelsson, Erik A1 - Deary, Ian J A1 - Mägi, Reedik A1 - Vandenput, Liesbeth A1 - van der Harst, Pim A1 - Desch, Karl C A1 - Kooner, Jaspal S A1 - Ohlsson, Claes A1 - Hayward, Caroline A1 - Lehtimäki, Terho A1 - Shuldiner, Alan R A1 - Arnett, Donna K A1 - Beilin, Lawrence J A1 - Robino, Antonietta A1 - Froguel, Philippe A1 - Pirastu, Mario A1 - Jess, Tine A1 - Koenig, Wolfgang A1 - Loos, Ruth J F A1 - Evans, Denis A A1 - Schmidt, Helena A1 - Smith, George Davey A1 - Slagboom, P Eline A1 - Eiriksdottir, Gudny A1 - Morris, Andrew P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Nolte, Ilja M A1 - Boerwinkle, Eric A1 - Visvikis-Siest, Sophie A1 - Reiner, Alex P A1 - Gross, Myron A1 - Bis, Joshua C A1 - Franke, Lude A1 - Franco, Oscar H A1 - Benjamin, Emelia J A1 - Chasman, Daniel I A1 - Dupuis, Josée A1 - Snieder, Harold A1 - Dehghan, Abbas A1 - Alizadeh, Behrooz Z AB -

C-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.

VL - 103 IS - 5 ER - TY - JOUR T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. JF - Nat Commun Y1 - 2018 A1 - Teumer, Alexander A1 - Chaker, Layal A1 - Groeneweg, Stefan A1 - Li, Yong A1 - Di Munno, Celia A1 - Barbieri, Caterina A1 - Schultheiss, Ulla T A1 - Traglia, Michela A1 - Ahluwalia, Tarunveer S A1 - Akiyama, Masato A1 - Appel, Emil Vincent R A1 - Arking, Dan E A1 - Arnold, Alice A1 - Astrup, Arne A1 - Beekman, Marian A1 - Beilby, John P A1 - Bekaert, Sofie A1 - Boerwinkle, Eric A1 - Brown, Suzanne J A1 - De Buyzere, Marc A1 - Campbell, Purdey J A1 - Ceresini, Graziano A1 - Cerqueira, Charlotte A1 - Cucca, Francesco A1 - Deary, Ian J A1 - Deelen, Joris A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Eriksson, Johan G A1 - Ferrrucci, Luigi A1 - Fiers, Tom A1 - Fiorillo, Edoardo A1 - Ford, Ian A1 - Fox, Caroline S A1 - Fuchsberger, Christian A1 - Galesloot, Tessel E A1 - Gieger, Christian A1 - Gögele, Martin A1 - De Grandi, Alessandro A1 - Grarup, Niels A1 - Greiser, Karin Halina A1 - Haljas, Kadri A1 - Hansen, Torben A1 - Harris, Sarah E A1 - van Heemst, Diana A1 - den Heijer, Martin A1 - Hicks, Andrew A A1 - den Hollander, Wouter A1 - Homuth, Georg A1 - Hui, Jennie A1 - Ikram, M Arfan A1 - Ittermann, Till A1 - Jensen, Richard A A1 - Jing, Jiaojiao A1 - Jukema, J Wouter A1 - Kajantie, Eero A1 - Kamatani, Yoichiro A1 - Kasbohm, Elisa A1 - Kaufman, Jean-Marc A1 - Kiemeney, Lambertus A A1 - Kloppenburg, Margreet A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Lahti, Jari A1 - Lapauw, Bruno A1 - Li, Shuo A1 - Liewald, David C M A1 - Lim, Ee Mun A1 - Linneberg, Allan A1 - Marina, Michela A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Medenwald, Daniel A1 - Meisinger, Christa A1 - Meulenbelt, Ingrid A1 - De Meyer, Tim A1 - Meyer zu Schwabedissen, Henriette E A1 - Mikolajczyk, Rafael A1 - Moed, Matthijs A1 - Netea-Maier, Romana T A1 - Nolte, Ilja M A1 - Okada, Yukinori A1 - Pala, Mauro A1 - Pattaro, Cristian A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Porcu, Eleonora A1 - Postmus, Iris A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Ramos, Yolande F M A1 - Rawal, Rajesh A1 - Redmond, Paul A1 - Richards, J Brent A1 - Rietzschel, Ernst R A1 - Rivadeneira, Fernando A1 - Roef, Greet A1 - Rotter, Jerome I A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Selvin, Elizabeth A1 - Slagboom, P Eline A1 - Soranzo, Nicole A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Starr, John M A1 - Stott, David J A1 - Taes, Youri A1 - Taliun, Daniel A1 - Tanaka, Toshiko A1 - Thuesen, Betina A1 - Tiller, Daniel A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Visser, W Edward A1 - Walsh, John P A1 - Wilson, Scott G A1 - Wolffenbuttel, Bruce H R A1 - Yang, Qiong A1 - Zheng, Hou-Feng A1 - Cappola, Anne A1 - Peeters, Robin P A1 - Naitza, Silvia A1 - Völzke, Henry A1 - Sanna, Serena A1 - Köttgen, Anna A1 - Visser, Theo J A1 - Medici, Marco AB -

Thyroid 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium. JF - PLoS One Y1 - 2018 A1 - de Oliveira Otto, Marcia C A1 - Lemaitre, Rozenn N A1 - Sun, Qi A1 - King, Irena B A1 - Wu, Jason H Y A1 - Manichaikul, Ani A1 - Rich, Stephen S A1 - Tsai, Michael Y A1 - Chen, Y D A1 - Fornage, Myriam A1 - Weihua, Guan A1 - Aslibekyan, Stella A1 - Irvin, Marguerite R A1 - Kabagambe, Edmond K A1 - Arnett, Donna K A1 - Jensen, Majken K A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Steffen, Lyn M A1 - Smith, Caren E A1 - Riserus, Ulf A1 - Lind, Lars A1 - Hu, Frank B A1 - Rimm, Eric B A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Fatty Acids KW - Genome-Wide Association Study KW - Humans KW - Introns KW - Lactase KW - Myosins KW - Polymorphism, Single Nucleotide KW - Sphingomyelins KW - Sphingosine N-Acyltransferase KW - Tumor Suppressor Proteins AB -

BACKGROUND: 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.

VL - 13 IS - 5 ER - TY - JOUR T1 - Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy. JF - Sci Rep Y1 - 2018 A1 - Napier, Melanie D A1 - Franceschini, Nora A1 - Gondalia, Rahul A1 - Stewart, James D A1 - Méndez-Giráldez, Rául A1 - Sitlani, Colleen M A1 - Seyerle, Amanda A A1 - Highland, Heather M A1 - Li, Yun A1 - Wilhelmsen, Kirk C A1 - Yan, Song A1 - Duan, Qing A1 - Roach, Jeffrey A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Heckbert, Susan R A1 - Rotter, Jerome I A1 - North, Kari E A1 - Reiner, Alexander P A1 - Zhang, Zhu-Ming A1 - Tinker, Lesley F A1 - Liao, Duanping A1 - Laurie, Cathy C A1 - Gogarten, Stephanie M A1 - Lin, Henry J A1 - Brody, Jennifer A A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Whitsel, Eric A AB -

The 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.

VL - 8 IS - 1 ER - TY - JOUR T1 - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. JF - Nat Commun Y1 - 2018 A1 - Jiang, Xia A1 - O'Reilly, Paul F A1 - Aschard, Hugues A1 - Hsu, Yi-Hsiang A1 - Richards, J Brent A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Karasik, David A1 - Pilz, Stefan A1 - Berry, Diane A1 - Kestenbaum, Bryan A1 - Zheng, Jusheng A1 - Luan, Jianan A1 - Sofianopoulou, Eleni A1 - Streeten, Elizabeth A A1 - Albanes, Demetrius A1 - Lutsey, Pamela L A1 - Yao, Lu A1 - Tang, Weihong A1 - Econs, Michael J A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Zhou, Ang A1 - Power, Chris A1 - McCarthy, Mark I A1 - Michos, Erin D A1 - Boerwinkle, Eric A1 - Weinstein, Stephanie J A1 - Freedman, Neal D A1 - Huang, Wen-Yi A1 - van Schoor, Natasja M A1 - van der Velde, Nathalie A1 - Groot, Lisette C P G M de A1 - Enneman, Anke A1 - Cupples, L Adrienne A1 - Booth, Sarah L A1 - Vasan, Ramachandran S A1 - Liu, Ching-Ti A1 - Zhou, Yanhua A1 - Ripatti, Samuli A1 - Ohlsson, Claes A1 - Vandenput, Liesbeth A1 - Lorentzon, Mattias A1 - Eriksson, Johan G A1 - Shea, M Kyla A1 - Houston, Denise K A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Ferrucci, Luigi A1 - Peacock, Munro A1 - Gieger, Christian A1 - Beekman, Marian A1 - Slagboom, Eline A1 - Deelen, Joris A1 - Heemst, Diana van A1 - Kleber, Marcus E A1 - März, Winfried A1 - de Boer, Ian H A1 - Wood, Alexis C A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Robinson-Cohen, Cassianne A1 - den Heijer, Martin A1 - Jarvelin, Marjo-Riitta A1 - Cavadino, Alana A1 - Joshi, Peter K A1 - Wilson, James F A1 - Hayward, Caroline A1 - Lind, Lars A1 - Michaëlsson, Karl A1 - Trompet, Stella A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Broer, Linda A1 - Zgaga, Lina A1 - Campbell, Harry A1 - Theodoratou, Evropi A1 - Farrington, Susan M A1 - Timofeeva, Maria A1 - Dunlop, Malcolm G A1 - Valdes, Ana M A1 - Tikkanen, Emmi A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Mikkilä, Vera A1 - Ikram, M Arfan A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Forouhi, Nita G A1 - Gundersen, Thomas E A1 - Khaw, Kay-Tee A1 - Butterworth, Adam S A1 - Danesh, John A1 - Spector, Timothy A1 - Wang, Thomas J A1 - Hyppönen, Elina A1 - Kraft, Peter A1 - Kiel, Douglas P AB -

Vitamin 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. JF - Nat Commun Y1 - 2018 A1 - Vojinovic, Dina A1 - Adams, Hieab H A1 - Jian, Xueqiu A1 - Yang, Qiong A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Teumer, Alexander A1 - Scholz, Markus A1 - Armstrong, Nicola J A1 - Hofer, Edith A1 - Saba, Yasaman A1 - Luciano, Michelle A1 - Bernard, Manon A1 - Trompet, Stella A1 - Yang, Jingyun A1 - Gillespie, Nathan A A1 - van der Lee, Sven J A1 - Neumann, Alexander A1 - Ahmad, Shahzad A1 - Andreassen, Ole A A1 - Ames, David A1 - Amin, Najaf A1 - Arfanakis, Konstantinos A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Beiser, Alexa S A1 - Beyer, Frauke A1 - Brodaty, Henry A1 - Bryan, R Nick A1 - Bülow, Robin A1 - Dale, Anders M A1 - De Jager, Philip L A1 - Deary, Ian J A1 - DeCarli, Charles A1 - Fleischman, Debra A A1 - Gottesman, Rebecca F A1 - van der Grond, Jeroen A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Homuth, Georg A1 - Knopman, David S A1 - Kwok, John B A1 - Lewis, Cora E A1 - Li, Shuo A1 - Loeffler, Markus A1 - Lopez, Oscar L A1 - Maillard, Pauline A1 - El Marroun, Hanan A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Muetzel, Ryan L A1 - Nauck, Matthias A1 - Nyquist, Paul A A1 - Panizzon, Matthew S A1 - Pausova, Zdenka A1 - Psaty, Bruce M A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Royle, Natalie A1 - Satizabal, Claudia L A1 - Schmidt, Reinhold A1 - Schofield, Peter R A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Stott, David J A1 - Thalamuthu, Anbupalam A1 - Uitterlinden, André G A1 - Valdés Hernández, Maria C A1 - Vernooij, Meike W A1 - Wen, Wei A1 - White, Tonya A1 - Witte, A Veronica A1 - Wittfeld, Katharina A1 - Wright, Margaret J A1 - Yanek, Lisa R A1 - Tiemeier, Henning A1 - Kremen, William S A1 - Bennett, David A A1 - Jukema, J Wouter A1 - Paus, Tomáš A1 - Wardlaw, Joanna M A1 - Schmidt, Helena A1 - Sachdev, Perminder S A1 - Villringer, Arno A1 - Grabe, Hans Jörgen A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Fornage, Myriam AB -

The 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. JF - Circulation Y1 - 2018 A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - de Vries, Paul S A1 - Marten, Jonathan A1 - Mastrangelo, Michael A A1 - Song, Ci A1 - Pankratz, Nathan A1 - Ward-Caviness, Cavin K A1 - Yanek, Lisa R A1 - Trompet, Stella A1 - Delgado, Graciela E A1 - Guo, Xiuqing A1 - Bartz, Traci M A1 - Martinez-Perez, Angel A1 - Germain, Marine A1 - de Haan, Hugoline G A1 - Ozel, Ayse B A1 - Polasek, Ozren A1 - Smith, Albert V A1 - Eicher, John D A1 - Reiner, Alex P A1 - Tang, Weihong A1 - Davies, Neil M A1 - Stott, David J A1 - Rotter, Jerome I A1 - Tofler, Geoffrey H A1 - Boerwinkle, Eric A1 - de Maat, Moniek P M A1 - Kleber, Marcus E A1 - Welsh, Paul A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Vaidya, Dhananjay A1 - Soria, José Manuel A1 - Suchon, Pierre A1 - van Hylckama Vlieg, Astrid A1 - Desch, Karl C A1 - Kolcic, Ivana A1 - Joshi, Peter K A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Campbell, Harry A1 - Rudan, Igor A1 - Becker, Diane M A1 - Li, Jun Z A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Morange, Pierre-Emmanuel A1 - McKnight, Barbara A1 - Chong, Michael R A1 - Fernandez-Cadenas, Israel A1 - Rosand, Jonathan A1 - Lindgren, Arne A1 - Gudnason, Vilmundur A1 - Wilson, James F A1 - Hayward, Caroline A1 - Ginsburg, David A1 - Fornage, Myriam A1 - Rosendaal, Frits R A1 - Souto, Juan Carlos A1 - Becker, Lewis C A1 - Jenny, Nancy S A1 - März, Winfried A1 - Jukema, J Wouter A1 - Dehghan, Abbas A1 - Trégouët, David-Alexandre A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Strachan, David P A1 - Lowenstein, Charles J A1 - Smith, Nicholas L AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study). JF - J Am Heart Assoc Y1 - 2018 A1 - Tereshchenko, Larisa G A1 - Sotoodehnia, Nona A1 - Sitlani, Colleen M A1 - Ashar, Foram N A1 - Kabir, Muammar A1 - Biggs, Mary L A1 - Morley, Michael P A1 - Waks, Jonathan W A1 - Soliman, Elsayed Z A1 - Buxton, Alfred E A1 - Biering-Sørensen, Tor A1 - Solomon, Scott D A1 - Post, Wendy S A1 - Cappola, Thomas P A1 - Siscovick, David S A1 - Arking, Dan E AB -

BACKGROUND: 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.

VL - 7 IS - 8 ER - TY - JOUR T1 - Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. JF - PLoS Genet Y1 - 2018 A1 - Suri, Pradeep A1 - Palmer, Melody R A1 - Tsepilov, Yakov A A1 - Freidin, Maxim B A1 - Boer, Cindy G A1 - Yau, Michelle S A1 - Evans, Daniel S A1 - Gelemanovic, Andrea A1 - Bartz, Traci M A1 - Nethander, Maria A1 - Arbeeva, Liubov A1 - Karssen, Lennart A1 - Neogi, Tuhina A1 - Campbell, Archie A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Marshall, Lynn M A1 - Orwoll, Eric A1 - Uitterlinden, Andre A1 - Rotter, Jerome I A1 - Lauc, Gordan A1 - Psaty, Bruce M A1 - Karlsson, Magnus K A1 - Lane, Nancy E A1 - Jarvik, Gail P A1 - Polasek, Ozren A1 - Hochberg, Marc A1 - Jordan, Joanne M A1 - van Meurs, Joyce B J A1 - Jackson, Rebecca A1 - Nielson, Carrie M A1 - Mitchell, Braxton D A1 - Smith, Blair H A1 - Hayward, Caroline A1 - Smith, Nicholas L A1 - Aulchenko, Yurii S A1 - Williams, Frances M K AB -

Back 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).

VL - 14 IS - 9 ER - TY - JOUR T1 - Genome-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. JF - Pharmacogenomics J Y1 - 2018 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Noordam, Raymond A1 - Avery, Christie L A1 - Bis, Joshua C A1 - Floyd, James S A1 - Li, Jin A1 - Limdi, Nita A A1 - Srinivasasainagendra, Vinodh A1 - Stewart, James A1 - de Mutsert, Renée A1 - Mook-Kanamori, Dennis O A1 - Lipovich, Leonard A1 - Kleinbrink, Erica L A1 - Smith, Albert A1 - Bartz, Traci M A1 - Whitsel, Eric A A1 - Uitterlinden, André G A1 - Wiggins, Kerri L A1 - Wilson, James G A1 - Zhi, Degui A1 - Stricker, Bruno H A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Lange, Leslie A AB -

We 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.

ER - TY - JOUR T1 - GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. JF - Nat Commun Y1 - 2018 A1 - Franceschini, Nora A1 - Giambartolomei, Claudia A1 - de Vries, Paul S A1 - Finan, Chris A1 - Bis, Joshua C A1 - Huntley, Rachael P A1 - Lovering, Ruth C A1 - Tajuddin, Salman M A1 - Winkler, Thomas W A1 - Graff, Misa A1 - Kavousi, Maryam A1 - Dale, Caroline A1 - Smith, Albert V A1 - Hofer, Edith A1 - van Leeuwen, Elisabeth M A1 - Nolte, Ilja M A1 - Lu, Lingyi A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Pitkänen, Niina A1 - Franzén, Oscar A1 - Joshi, Peter K A1 - Noordam, Raymond A1 - Marioni, Riccardo E A1 - Hwang, Shih-Jen A1 - Musani, Solomon K A1 - Schminke, Ulf A1 - Palmas, Walter A1 - Isaacs, Aaron A1 - Correa, Adolfo A1 - Zonderman, Alan B A1 - Hofman, Albert A1 - Teumer, Alexander A1 - Cox, Amanda J A1 - Uitterlinden, André G A1 - Wong, Andrew A1 - Smit, Andries J A1 - Newman, Anne B A1 - Britton, Annie A1 - Ruusalepp, Arno A1 - Sennblad, Bengt A1 - Hedblad, Bo A1 - Pasaniuc, Bogdan A1 - Penninx, Brenda W A1 - Langefeld, Carl D A1 - Wassel, Christina L A1 - Tzourio, Christophe A1 - Fava, Cristiano A1 - Baldassarre, Damiano A1 - O'Leary, Daniel H A1 - Teupser, Daniel A1 - Kuh, Diana A1 - Tremoli, Elena A1 - Mannarino, Elmo A1 - Grossi, Enzo A1 - Boerwinkle, Eric A1 - Schadt, Eric E A1 - Ingelsson, Erik A1 - Veglia, Fabrizio A1 - Rivadeneira, Fernando A1 - Beutner, Frank A1 - Chauhan, Ganesh A1 - Heiss, Gerardo A1 - Snieder, Harold A1 - Campbell, Harry A1 - Völzke, Henry A1 - Markus, Hugh S A1 - Deary, Ian J A1 - Jukema, J Wouter A1 - de Graaf, Jacqueline A1 - Price, Jacqueline A1 - Pott, Janne A1 - Hopewell, Jemma C A1 - Liang, Jingjing A1 - Thiery, Joachim A1 - Engmann, Jorgen A1 - Gertow, Karl A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Dhana, Klodian A1 - Kiemeney, Lambertus A L M A1 - Lind, Lars A1 - Raffield, Laura M A1 - Launer, Lenore J A1 - Holdt, Lesca M A1 - Dörr, Marcus A1 - Dichgans, Martin A1 - Traylor, Matthew A1 - Sitzer, Matthias A1 - Kumari, Meena A1 - Kivimaki, Mika A1 - Nalls, Mike A A1 - Melander, Olle A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Rueda-Ochoa, Oscar L A1 - Roussos, Panos A1 - Whincup, Peter H A1 - Amouyel, Philippe A1 - Giral, Philippe A1 - Anugu, Pramod A1 - Wong, Quenna A1 - Malik, Rainer A1 - Rauramaa, Rainer A1 - Burkhardt, Ralph A1 - Hardy, Rebecca A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Morris, Richard W A1 - Strawbridge, Rona J A1 - Wannamethee, S Goya A1 - Hägg, Sara A1 - Shah, Sonia A1 - McLachlan, Stela A1 - Trompet, Stella A1 - Seshadri, Sudha A1 - Kurl, Sudhir A1 - Heckbert, Susan R A1 - Ring, Susan A1 - Harris, Tamara B A1 - Lehtimäki, Terho A1 - Galesloot, Tessel E A1 - Shah, Tina A1 - de Faire, Ulf A1 - Plagnol, Vincent A1 - Rosamond, Wayne D A1 - Post, Wendy A1 - Zhu, Xiaofeng A1 - Zhang, Xiaoling A1 - Guo, Xiuqing A1 - Saba, Yasaman A1 - Dehghan, Abbas A1 - Seldenrijk, Adrie A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Lawlor, Deborah A A1 - Mook-Kanamori, Dennis O A1 - Bowden, Donald W A1 - Schmidt, Helena A1 - Wilson, James F A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Wardlaw, Joanna M A1 - Deanfield, John A1 - Halcox, Julian A1 - Lyytikäinen, Leo-Pekka A1 - Loeffler, Markus A1 - Evans, Michele K A1 - Debette, Stephanie A1 - Humphries, Steve E A1 - Völker, Uwe A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Björkegren, Johan L M A1 - Casas, Juan P A1 - O'Donnell, Christopher J KW - ADAMTS9 Protein KW - Amino Acid Oxidoreductases KW - Carotid Intima-Media Thickness KW - Coronary Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Lod Score KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors AB -

Carotid 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stephanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I AB -

Genome-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).

VL - 102 IS - 3 ER - TY - JOUR T1 - Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. JF - Nat Commun Y1 - 2018 A1 - Tin, Adrienne A1 - Li, Yong A1 - Brody, Jennifer A A1 - Nutile, Teresa A1 - Chu, Audrey Y A1 - Huffman, Jennifer E A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Robinson-Cohen, Cassianne A1 - Mace, Aurelien A1 - Liu, Jun A1 - Demirkan, Ayse A1 - Sorice, Rossella A1 - Sedaghat, Sanaz A1 - Swen, Melody A1 - Yu, Bing A1 - Ghasemi, Sahar A1 - Teumer, Alexanda A1 - Vollenweider, Peter A1 - Ciullo, Marina A1 - Li, Meng A1 - Uitterlinden, André G A1 - Kraaij, Robert A1 - Amin, Najaf A1 - van Rooij, Jeroen A1 - Kutalik, Zoltán A1 - Dehghan, Abbas A1 - McKnight, Barbara A1 - van Duijn, Cornelia M A1 - Morrison, Alanna A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fox, Caroline S A1 - Woodward, Owen M A1 - Köttgen, Anna KW - Exome KW - Genetic Predisposition to Disease KW - Glucose Transport Proteins, Facilitative KW - Humans KW - Kidney Function Tests KW - Meta-Analysis as Topic KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Protein Structure, Secondary KW - Uric Acid AB -

Elevated 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - {Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects JF - Am J Hum Genet Y1 - 2018 A1 - Medina-Gomez, C. A1 - Kemp, J. P. A1 - Trajanoska, K. A1 - Luan, J. A1 - Chesi, A. A1 - Ahluwalia, T. S. A1 - Mook-Kanamori, D. O. A1 - Ham, A. A1 - Hartwig, F. P. A1 - Evans, D. S. A1 - Joro, R. A1 - Nedeljkovic, I. A1 - Zheng, H. F. A1 - Zhu, K. A1 - Atalay, M. A1 - Liu, C. T. A1 - Nethander, M. A1 - Broer, L. A1 - Porleifsson, G. A1 - Mullin, B. H. A1 - Handelman, S. K. A1 - Nalls, M. A. A1 - Jessen, L. E. A1 - Heppe, D. H. M. A1 - Richards, J. B. A1 - Wang, C. A1 - Chawes, B. A1 - Schraut, K. E. A1 - Amin, N. A1 - Wareham, N. A1 - Karasik, D. A1 - Van der Velde, N. A1 - Ikram, M. A. A1 - Zemel, B. S. A1 - Zhou, Y. A1 - Carlsson, C. J. A1 - Liu, Y. A1 - McGuigan, F. E. A1 - Boer, C. G. A1 - B?nnelykke, K. A1 - Ralston, S. H. A1 - Robbins, J. A. A1 - Walsh, J. P. A1 - Zillikens, M. C. A1 - Langenberg, C. A1 - Li-Gao, R. A1 - Williams, F. M. K. A1 - Harris, T. B. A1 - Akesson, K. A1 - Jackson, R. D. A1 - Sigurdsson, G. A1 - den Heijer, M. A1 - van der Eerden, B. C. J. A1 - van de Peppel, J. A1 - Spector, T. D. A1 - Pennell, C. A1 - Horta, B. L. A1 - Felix, J. F. A1 - Zhao, J. H. A1 - Wilson, S. G. A1 - de Mutsert, R. A1 - Bisgaard, H. A1 - Styrk?rsd?ttir, U. A1 - Jaddoe, V. W. A1 - Orwoll, E. A1 - Lakka, T. A. A1 - Scott, R. A1 - Grant, S. F. A. A1 - Lorentzon, M. A1 - van Duijn, C. M. A1 - Wilson, J. F. A1 - Stefansson, K. A1 - Psaty, B. M. A1 - Kiel, D. P. A1 - Ohlsson, C. A1 - Ntzani, E. A1 - van Wijnen, A. J. A1 - Forgetta, V. A1 - Ghanbari, M. A1 - Logan, J. G. A1 - Williams, G. R. A1 - Bassett, J. H. D. A1 - Croucher, P. I. A1 - Evangelou, E. A1 - Uitterlinden, A. G. A1 - Ackert-Bicknell, C. L. A1 - Tobias, J. H. A1 - Evans, D. M. A1 - Rivadeneira, F. AB - Bone 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. VL - 102 ER - TY - JOUR T1 - Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study). JF - Circ Heart Fail Y1 - 2018 A1 - Hammond, Christa A A1 - Blades, Natalie J A1 - Chaudhry, Sarwat I A1 - Dodson, John A A1 - Longstreth, W T A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Arnold, Alice M A1 - Dublin, Sascha A1 - Sitlani, Colleen M A1 - Gardin, Julius M A1 - Thielke, Stephen M A1 - Nanna, Michael G A1 - Gottesman, Rebecca F A1 - Newman, Anne B A1 - Thacker, Evan L AB -

BACKGROUND: 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.

VL - 11 IS - 3 ER - TY - JOUR T1 - Low thyroid function is not associated with an accelerated deterioration in renal function. JF - Nephrol Dial Transplant Y1 - 2018 A1 - Meuwese, Christiaan L A1 - van Diepen, Merel A1 - Cappola, Anne R A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Bauer, Douglas C A1 - Fried, Linda P A1 - Iacoviello, Massimo A1 - Vaes, Bert A1 - Degryse, Jean A1 - Khaw, Kay-Tee A1 - Luben, Robert N A1 - Asvold, Bjørn O A1 - Bjøro, Trine A1 - Vatten, Lars J A1 - de Craen, Anton J M A1 - Trompet, Stella A1 - Iervasi, Giorgio A1 - Molinaro, Sabrina A1 - Ceresini, Graziano A1 - Ferrucci, Luigi A1 - Dullaart, Robin P F A1 - Bakker, Stephan J L A1 - Jukema, J Wouter A1 - Kearney, Patricia M A1 - Stott, David J A1 - Peeters, Robin P A1 - Franco, Oscar H A1 - Völzke, Henry A1 - Walsh, John P A1 - Bremner, Alexandra A1 - Sgarbi, José A A1 - Maciel, Rui M B A1 - Imaizumi, Misa A1 - Ohishi, Waka A1 - Dekker, Friedo W A1 - Rodondi, Nicolas A1 - Gussekloo, Jacobijn A1 - den Elzen, Wendy P J AB -

Background: 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.

ER - TY - JOUR T1 - Meta-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. JF - Br J Nutr Y1 - 2018 A1 - Xu, Jiayi A1 - Bartz, Traci M A1 - Chittoor, Geetha A1 - Eiriksdottir, Gudny A1 - Manichaikul, Ani W A1 - Sun, Fangui A1 - Terzikhan, Natalie A1 - Zhou, Xia A1 - Booth, Sarah L A1 - Brusselle, Guy G A1 - de Boer, Ian H A1 - Fornage, Myriam A1 - Frazier-Wood, Alexis C A1 - Graff, Mariaelisa A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Hou, Ruixue A1 - Houston, Denise K A1 - Jacobs, David R A1 - Kritchevsky, Stephen B A1 - Latourelle, Jeanne A1 - Lemaitre, Rozenn N A1 - Lutsey, Pamela L A1 - O'Connor, George A1 - Oelsner, Elizabeth C A1 - Pankow, James S A1 - Psaty, Bruce M A1 - Rohde, Rebecca R A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Lewis J A1 - Stricker, Bruno H A1 - Voruganti, V Saroja A1 - Wang, Thomas J A1 - Zillikens, M Carola A1 - Barr, R Graham A1 - Dupuis, Josée A1 - Gharib, Sina A A1 - Lahousse, Lies A1 - London, Stephanie J A1 - North, Kari E A1 - Smith, Albert V A1 - Steffen, Lyn M A1 - Hancock, Dana B A1 - Cassano, Patricia A AB -

The 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.

ER - TY - JOUR T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function. JF - Wellcome Open Res Y1 - 2018 A1 - Jackson, Victoria E A1 - Latourelle, Jeanne C A1 - Wain, Louise V A1 - Smith, Albert V A1 - Grove, Megan L A1 - Bartz, Traci M A1 - Obeidat, Ma'en A1 - Province, Michael A A1 - Gao, Wei A1 - Qaiser, Beenish A1 - Porteous, David J A1 - Cassano, Patricia A A1 - Ahluwalia, Tarunveer S A1 - Grarup, Niels A1 - Li, Jin A1 - Altmaier, Elisabeth A1 - Marten, Jonathan A1 - Harris, Sarah E A1 - Manichaikul, Ani A1 - Pottinger, Tess D A1 - Li-Gao, Ruifang A1 - Lind-Thomsen, Allan A1 - Mahajan, Anubha A1 - Lahousse, Lies A1 - Imboden, Medea A1 - Teumer, Alexander A1 - Prins, Bram A1 - Lyytikäinen, Leo-Pekka A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Sitlani, Colleen M A1 - Brody, Jennifer A A1 - Bossé, Yohan A1 - Timens, Wim A1 - Kraja, Aldi A1 - Loukola, Anu A1 - Tang, Wenbo A1 - Liu, Yongmei A1 - Bork-Jensen, Jette A1 - Justesen, Johanne M A1 - Linneberg, Allan A1 - Lange, Leslie A A1 - Rawal, Rajesh A1 - Karrasch, Stefan A1 - Huffman, Jennifer E A1 - Smith, Blair H A1 - Davies, Gail A1 - Burkart, Kristin M A1 - Mychaleckyj, Josyf C A1 - Bonten, Tobias N A1 - Enroth, Stefan A1 - Lind, Lars A1 - Brusselle, Guy G A1 - Kumar, Ashish A1 - Stubbe, Beate A1 - Kähönen, Mika A1 - Wyss, Annah B A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hao, Ke A1 - Rantanen, Taina A1 - Kritchevsky, Stephen B A1 - Lohman, Kurt A1 - Skaaby, Tea A1 - Pisinger, Charlotta A1 - Hansen, Torben A1 - Schulz, Holger A1 - Polasek, Ozren A1 - Campbell, Archie A1 - Starr, John M A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Johansson, Asa A1 - Ingelsson, Erik A1 - Uitterlinden, André G A1 - Weiss, Stefan A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Gharib, Sina A A1 - Sin, Don D A1 - Taylor, Kent D A1 - O'Connor, George T A1 - Kaprio, Jaakko A1 - Harris, Tamara B A1 - Pederson, Oluf A1 - Vestergaard, Henrik A1 - Wilson, James G A1 - Strauch, Konstantin A1 - Hayward, Caroline A1 - Kerr, Shona A1 - Deary, Ian J A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Gyllensten, Ulf A1 - Morris, Andrew P A1 - Ikram, M Arfan A1 - Probst-Hensch, Nicole A1 - Gläser, Sven A1 - Zeggini, Eleftheria A1 - Lehtimäki, Terho A1 - Strachan, David P A1 - Dupuis, Josée A1 - Morrison, Alanna C A1 - Hall, Ian P A1 - Tobin, Martin D A1 - London, Stephanie J AB -

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.

VL - 3 ER - TY - JOUR T1 - Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. JF - Nat Genet Y1 - 2018 A1 - Demenais, Florence A1 - Margaritte-Jeannin, Patricia A1 - Barnes, Kathleen C A1 - Cookson, William O C A1 - Altmüller, Janine A1 - Ang, Wei A1 - Barr, R Graham A1 - Beaty, Terri H A1 - Becker, Allan B A1 - Beilby, John A1 - Bisgaard, Hans A1 - Bjornsdottir, Unnur Steina A1 - Bleecker, Eugene A1 - Bønnelykke, Klaus A1 - Boomsma, Dorret I A1 - Bouzigon, Emmanuelle A1 - Brightling, Christopher E A1 - Brossard, Myriam A1 - Brusselle, Guy G A1 - Burchard, Esteban A1 - Burkart, Kristin M A1 - Bush, Andrew A1 - Chan-Yeung, Moira A1 - Chung, Kian Fan A1 - Couto Alves, Alexessander A1 - Curtin, John A A1 - Custovic, Adnan A1 - Daley, Denise A1 - de Jongste, Johan C A1 - Del-Rio-Navarro, Blanca E A1 - Donohue, Kathleen M A1 - Duijts, Liesbeth A1 - Eng, Celeste A1 - Eriksson, Johan G A1 - Farrall, Martin A1 - Fedorova, Yuliya A1 - Feenstra, Bjarke A1 - Ferreira, Manuel A A1 - Freidin, Maxim B A1 - Gajdos, Zofia A1 - Gauderman, Jim A1 - Gehring, Ulrike A1 - Geller, Frank A1 - Genuneit, Jon A1 - Gharib, Sina A A1 - Gilliland, Frank A1 - Granell, Raquel A1 - Graves, Penelope E A1 - Gudbjartsson, Daniel F A1 - Haahtela, Tari A1 - Heckbert, Susan R A1 - Heederik, Dick A1 - Heinrich, Joachim A1 - Heliövaara, Markku A1 - Henderson, John A1 - Himes, Blanca E A1 - Hirose, Hiroshi A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Holt, Patrick A1 - Hottenga, Jouke A1 - Hudson, Thomas J A1 - Hui, Jennie A1 - Imboden, Medea A1 - Ivanov, Vladimir A1 - Jaddoe, Vincent W V A1 - James, Alan A1 - Janson, Christer A1 - Jarvelin, Marjo-Riitta A1 - Jarvis, Deborah A1 - Jones, Graham A1 - Jonsdottir, Ingileif A1 - Jousilahti, Pekka A1 - Kabesch, Michael A1 - Kähönen, Mika A1 - Kantor, David B A1 - Karunas, Alexandra S A1 - Khusnutdinova, Elza A1 - Koppelman, Gerard H A1 - Kozyrskyj, Anita L A1 - Kreiner, Eskil A1 - Kubo, Michiaki A1 - Kumar, Rajesh A1 - Kumar, Ashish A1 - Kuokkanen, Mikko A1 - Lahousse, Lies A1 - Laitinen, Tarja A1 - Laprise, Catherine A1 - Lathrop, Mark A1 - Lau, Susanne A1 - Lee, Young-Ae A1 - Lehtimäki, Terho A1 - Letort, Sébastien A1 - Levin, Albert M A1 - Li, Guo A1 - Liang, Liming A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Loth, Daan W A1 - Manichaikul, Ani A1 - Marenholz, Ingo A1 - Martinez, Fernando J A1 - Matheson, Melanie C A1 - Mathias, Rasika A A1 - Matsumoto, Kenji A1 - Mbarek, Hamdi A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Melén, Erik A1 - Meyers, Deborah A1 - Michel, Sven A1 - Mohamdi, Hamida A1 - Musk, Arthur W A1 - Myers, Rachel A A1 - Nieuwenhuis, Maartje A E A1 - Noguchi, Emiko A1 - O'Connor, George T A1 - Ogorodova, Ludmila M A1 - Palmer, Cameron D A1 - Palotie, Aarno A1 - Park, Julie E A1 - Pennell, Craig E A1 - Pershagen, Göran A1 - Polonikov, Alexey A1 - Postma, Dirkje S A1 - Probst-Hensch, Nicole A1 - Puzyrev, Valery P A1 - Raby, Benjamin A A1 - Raitakari, Olli T A1 - Ramasamy, Adaikalavan A1 - Rich, Stephen S A1 - Robertson, Colin F A1 - Romieu, Isabelle A1 - Salam, Muhammad T A1 - Salomaa, Veikko A1 - Schlünssen, Vivi A1 - Scott, Robert A1 - Selivanova, Polina A A1 - Sigsgaard, Torben A1 - Simpson, Angela A1 - Siroux, Valérie A1 - Smith, Lewis J A1 - Solodilova, Maria A1 - Standl, Marie A1 - Stefansson, Kari A1 - Strachan, David P A1 - Stricker, Bruno H A1 - Takahashi, Atsushi A1 - Thompson, Philip J A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiesler, Carla M T A1 - Torgerson, Dara G A1 - Tsunoda, Tatsuhiko A1 - Uitterlinden, André G A1 - van der Valk, Ralf J P A1 - Vaysse, Amaury A1 - Vedantam, Sailaja A1 - von Berg, Andrea A1 - von Mutius, Erika A1 - Vonk, Judith M A1 - Waage, Johannes A1 - Wareham, Nick J A1 - Weiss, Scott T A1 - White, Wendy B A1 - Wickman, Magnus A1 - Widen, Elisabeth A1 - Willemsen, Gonneke A1 - Williams, L Keoki A1 - Wouters, Inge M A1 - Yang, James J A1 - Zhao, Jing Hua A1 - Moffatt, Miriam F A1 - Ober, Carole A1 - Nicolae, Dan L AB -

We 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.

VL - 50 IS - 1 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke 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.

VL - 50 IS - 4 ER - TY - JOUR T1 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -

Atrial 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.

VL - 50 IS - 9 ER - TY - JOUR T1 - Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. JF - Nat Commun Y1 - 2018 A1 - Wyss, Annah B A1 - Sofer, Tamar A1 - Lee, Mi Kyeong A1 - Terzikhan, Natalie A1 - Nguyen, Jennifer N A1 - Lahousse, Lies A1 - Latourelle, Jeanne C A1 - Smith, Albert Vernon A1 - Bartz, Traci M A1 - Feitosa, Mary F A1 - Gao, Wei A1 - Ahluwalia, Tarunveer S A1 - Tang, Wenbo A1 - Oldmeadow, Christopher A1 - Duan, Qing A1 - de Jong, Kim A1 - Wojczynski, Mary K A1 - Wang, Xin-Qun A1 - Noordam, Raymond A1 - Hartwig, Fernando Pires A1 - Jackson, Victoria E A1 - Wang, Tianyuan A1 - Obeidat, Ma'en A1 - Hobbs, Brian D A1 - Huan, Tianxiao A1 - Gui, Hongsheng A1 - Parker, Margaret M A1 - Hu, Donglei A1 - Mogil, Lauren S A1 - Kichaev, Gleb A1 - Jin, Jianping A1 - Graff, Mariaelisa A1 - Harris, Tamara B A1 - Kalhan, Ravi A1 - Heckbert, Susan R A1 - Paternoster, Lavinia A1 - Burkart, Kristin M A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Wilson, James G A1 - Vonk, Judith M A1 - Sanders, Jason L A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Menezes, Ana Maria Baptista A1 - Adams, Hieab H H A1 - van den Berge, Maarten A1 - Joehanes, Roby A1 - Levin, Albert M A1 - Liberto, Jennifer A1 - Launer, Lenore J A1 - Morrison, Alanna C A1 - Sitlani, Colleen M A1 - Celedón, Juan C A1 - Kritchevsky, Stephen B A1 - Scott, Rodney J A1 - Christensen, Kaare A1 - Rotter, Jerome I A1 - Bonten, Tobias N A1 - Wehrmeister, Fernando César A1 - Bossé, Yohan A1 - Xiao, Shujie A1 - Oh, Sam A1 - Franceschini, Nora A1 - Brody, Jennifer A A1 - Kaplan, Robert C A1 - Lohman, Kurt A1 - McEvoy, Mark A1 - Province, Michael A A1 - Rosendaal, Frits R A1 - Taylor, Kent D A1 - Nickle, David C A1 - Williams, L Keoki A1 - Burchard, Esteban G A1 - Wheeler, Heather E A1 - Sin, Don D A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Myers, Richard H A1 - O'Connor, George A1 - Hansen, Torben A1 - Laurie, Cathy C A1 - Cassano, Patricia A A1 - Sung, Joohon A1 - Kim, Woo Jin A1 - Attia, John R A1 - Lange, Leslie A1 - Boezen, H Marike A1 - Thyagarajan, Bharat A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Horta, Bernardo Lessa A1 - Uitterlinden, André G A1 - Im, Hae Kyung A1 - Cho, Michael H A1 - Brusselle, Guy G A1 - Gharib, Sina A A1 - Dupuis, Josée A1 - Manichaikul, Ani A1 - London, Stephanie J AB -

Nearly 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. JF - Am J Respir Cell Mol Biol Y1 - 2018 A1 - Chen, Han A1 - Cade, Brian E A1 - Gleason, Kevin J A1 - Bjonnes, Andrew C A1 - Stilp, Adrienne M A1 - Sofer, Tamar A1 - Conomos, Matthew P A1 - Ancoli-Israel, Sonia A1 - Arens, Raanan A1 - Azarbarzin, Ali A1 - Bell, Graeme I A1 - Below, Jennifer E A1 - Chun, Sung A1 - Evans, Daniel S A1 - Ewert, Ralf A1 - Frazier-Wood, Alexis C A1 - Gharib, Sina A A1 - Haba-Rubio, José A1 - Hagen, Erika W A1 - Heinzer, Raphael A1 - Hillman, David R A1 - Johnson, W Craig A1 - Kutalik, Zoltán A1 - Lane, Jacqueline M A1 - Larkin, Emma K A1 - Lee, Seung Ku A1 - Liang, Jingjing A1 - Loredo, Jose S A1 - Mukherjee, Sutapa A1 - Palmer, Lyle J A1 - Papanicolaou, George J A1 - Penzel, Thomas A1 - Peppard, Paul E A1 - Post, Wendy S A1 - Ramos, Alberto R A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Sands, Scott A A1 - Shah, Neomi A A1 - Shin, Chol A1 - Stone, Katie L A1 - Stubbe, Beate A1 - Sul, Jae Hoon A1 - Tafti, Mehdi A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tranah, Gregory J A1 - Wang, Chaolong A1 - Wang, Heming A1 - Warby, Simon C A1 - Wellman, D Andrew A1 - Zee, Phyllis C A1 - Hanis, Craig L A1 - Laurie, Cathy C A1 - Gottlieb, Daniel J A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Sunyaev, Shamil R A1 - Saxena, Richa A1 - Lin, Xihong A1 - Redline, Susan AB -

Obstructive 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.

VL - 58 IS - 3 ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Göran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel AB -

Heavy 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.

VL - 13 IS - 6 ER - TY - JOUR T1 - Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association. JF - Am J Respir Crit Care Med Y1 - 2018 A1 - Xu, Jiayi A1 - Gaddis, Nathan C A1 - Bartz, Traci M A1 - Hou, Ruixue A1 - Manichaikul, Ani W A1 - Pankratz, Nathan A1 - Smith, Albert V A1 - Sun, Fangui A1 - Terzikhan, Natalie A1 - Markunas, Christina A A1 - Patchen, Bonnie K A1 - Schu, Matthew A1 - Beydoun, May A A1 - Brusselle, Guy G A1 - Eiriksdottir, Gudny A1 - Zhou, Xia A1 - Wood, Alexis C A1 - Graff, Mariaelisa A1 - Harris, Tamara B A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Launer, Lenore J A1 - Lemaitre, Rozenn N A1 - O'Connor, George A1 - Oelsner, Elizabeth C A1 - Psaty, Bruce M A1 - Ramachandran, Vasan S A1 - Rohde, Rebecca R A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Smith, Lewis J A1 - Tiemeier, Henning A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - Voruganti, V Saroja A1 - Xu, Hanfei A1 - Zilhão, Nuno R A1 - Fornage, Myriam A1 - Zillikens, M Carola A1 - London, Stephanie J A1 - Barr, R Graham A1 - Dupuis, Josée A1 - Gharib, Sina A A1 - Gudnason, Vilmundur A1 - Lahousse, Lies A1 - North, Kari E A1 - Steffen, Lyn M A1 - Cassano, Patricia A A1 - Hancock, Dana B AB -

RATIONALE: 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.

ER - TY - JOUR T1 - Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. JF - Environ Int Y1 - 2018 A1 - Wong, Jason Y Y A1 - Margolis, Helene G A1 - Machiela, Mitchell A1 - Zhou, Weiyin A1 - Odden, Michelle C A1 - Psaty, Bruce M A1 - Robbins, John A1 - Jones, Rena R A1 - Rotter, Jerome I A1 - Chanock, Stephen J A1 - Rothman, Nathaniel A1 - Lan, Qing A1 - Lee, Jennifer S AB -

BACKGROUND: 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.

VL - 116 ER - TY - JOUR T1 - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. JF - Nat Commun Y1 - 2018 A1 - van Setten, Jessica A1 - Brody, Jennifer A A1 - Jamshidi, Yalda A1 - Swenson, Brenton R A1 - Butler, Anne M A1 - Campbell, Harry A1 - Del Greco, Fabiola M A1 - Evans, Daniel S A1 - Gibson, Quince A1 - Gudbjartsson, Daniel F A1 - Kerr, Kathleen F A1 - Krijthe, Bouwe P A1 - Lyytikäinen, Leo-Pekka A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Ritchie, Marylyn D A1 - Robino, Antonietta A1 - Smith, Albert V A1 - Steri, Maristella A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Ulivi, Sheila A1 - Verweij, Niek A1 - Yin, Xiaoyan A1 - Arnar, David O A1 - Asselbergs, Folkert W A1 - Bader, Joel S A1 - Barnard, John A1 - Bis, Josh A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Bradford, Yuki A1 - Buckley, Brendan M A1 - Chung, Mina K A1 - Crawford, Dana A1 - den Hoed, Marcel A1 - Denny, Josh C A1 - Dominiczak, Anna F A1 - Ehret, Georg B A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Franke, Lude A1 - Harris, Tamara B A1 - Holm, Hilma A1 - Ilaria, Gandin A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kolcic, Ivana A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Launer, Lenore J A1 - Lin, Honghuang A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - Leach, Irene Mateo A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Münzel, Thomas A1 - Papanicolaou, George J A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Silva Aldana, Claudia T A1 - Sinner, Moritz F A1 - Smith, Jonathan D A1 - Snieder, Harold A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stott, David J A1 - Strauch, Konstantin A1 - Tarasov, Kirill V A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Jan Westra, Harm A1 - Wild, Philipp S A1 - Zeller, Tanja A1 - Alonso, Alvaro A1 - Avery, Christy L A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Cucca, Francesco A1 - Dörr, Marcus A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Munroe, Patricia B A1 - Parsa, Afshin A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Schnabel, Renate B A1 - Sinagra, Gianfranco A1 - Stefansson, Kari A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Wilson, James F A1 - Gharib, Sina A A1 - de Bakker, Paul I W A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Sotoodehnia, Nona AB -

Electrocardiographic 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Predictive 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. JF - PLoS One Y1 - 2018 A1 - Lorenz, Matthias W A1 - Gao, Lu A1 - Ziegelbauer, Kathrin A1 - Norata, Giuseppe Danilo A1 - Empana, Jean Philippe A1 - Schmidtmann, Irene A1 - Lin, Hung-Ju A1 - McLachlan, Stela A1 - Bokemark, Lena A1 - Ronkainen, Kimmo A1 - Amato, Mauro A1 - Schminke, Ulf A1 - Srinivasan, Sathanur R A1 - Lind, Lars A1 - Okazaki, Shuhei A1 - Stehouwer, Coen D A A1 - Willeit, Peter A1 - Polak, Joseph F A1 - Steinmetz, Helmuth A1 - Sander, Dirk A1 - Poppert, Holger A1 - Desvarieux, Moïse A1 - Ikram, M Arfan A1 - Johnsen, Stein Harald A1 - Staub, Daniel A1 - Sirtori, Cesare R A1 - Iglseder, Bernhard A1 - Beloqui, Oscar A1 - Engström, Gunnar A1 - Friera, Alfonso A1 - Rozza, Francesco A1 - Xie, Wuxiang A1 - Parraga, Grace A1 - Grigore, Liliana A1 - Plichart, Matthieu A1 - Blankenberg, Stefan A1 - Su, Ta-Chen A1 - Schmidt, Caroline A1 - Tuomainen, Tomi-Pekka A1 - Veglia, Fabrizio A1 - Völzke, Henry A1 - Nijpels, Giel A1 - Willeit, Johann A1 - Sacco, Ralph L A1 - Franco, Oscar H A1 - Uthoff, Heiko A1 - Hedblad, Bo A1 - Suarez, Carmen A1 - Izzo, Raffaele A1 - Zhao, Dong A1 - Wannarong, Thapat A1 - Catapano, Alberico A1 - Ducimetiere, Pierre A1 - Espinola-Klein, Christine A1 - Chien, Kuo-Liong A1 - Price, Jackie F A1 - Bergström, Göran A1 - Kauhanen, Jussi A1 - Tremoli, Elena A1 - Dörr, Marcus A1 - Berenson, Gerald A1 - Kitagawa, Kazuo A1 - Dekker, Jacqueline M A1 - Kiechl, Stefan A1 - Sitzer, Matthias A1 - Bickel, Horst A1 - Rundek, Tatjana A1 - Hofman, Albert A1 - Mathiesen, Ellisiv B A1 - Castelnuovo, Samuela A1 - Landecho, Manuel F A1 - Rosvall, Maria A1 - Gabriel, Rafael A1 - de Luca, Nicola A1 - Liu, Jing A1 - Baldassarre, Damiano A1 - Kavousi, Maryam A1 - de Groot, Eric A1 - Bots, Michiel L A1 - Yanez, David N A1 - Thompson, Simon G KW - Aged KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Female KW - Humans KW - Intersectoral Collaboration KW - Male KW - Middle Aged KW - Prognosis KW - Risk Factors AB -

AIMS: 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.

VL - 13 IS - 4 ER - TY - JOUR T1 - Protein and glycomic plasma markers for early detection of adenoma and colon cancer. JF - Gut Y1 - 2018 A1 - Rho, Jung-Hyun A1 - Ladd, Jon J A1 - Li, Christopher I A1 - Potter, John D A1 - Zhang, Yuzheng A1 - Shelley, David A1 - Shibata, David A1 - Coppola, Domenico A1 - Yamada, Hiroyuki A1 - Toyoda, Hidenori A1 - Tada, Toshifumi A1 - Kumada, Takashi A1 - Brenner, Dean E A1 - Hanash, Samir M A1 - Lampe, Paul D KW - Adaptor Proteins, Signal Transducing KW - Adenoma KW - Adult KW - Aged KW - Aged, 80 and over KW - Biomarkers, Tumor KW - CA-19-9 Antigen KW - Case-Control Studies KW - Colonic Neoplasms KW - Cytokine Receptor gp130 KW - Early Detection of Cancer KW - ErbB Receptors KW - Female KW - Humans KW - Hyaluronan Receptors KW - Lewis X Antigen KW - Male KW - Middle Aged KW - Oligosaccharides KW - Protein Array Analysis KW - von Willebrand Factor AB -

OBJECTIVE: 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.

VL - 67 IS - 3 ER - TY - JOUR T1 - Rare loss of function variants in candidate genes and risk of colorectal cancer. JF - Hum Genet Y1 - 2018 A1 - Rosenthal, Elisabeth A A1 - Shirts, Brian H A1 - Amendola, Laura M A1 - Horike-Pyne, Martha A1 - Robertson, Peggy D A1 - Hisama, Fuki M A1 - Bennett, Robin L A1 - Dorschner, Michael O A1 - Nickerson, Deborah A A1 - Stanaway, Ian B A1 - Nassir, Rami A1 - Vickers, Kathy T A1 - Li, Christopher A1 - Grady, William M A1 - Peters, Ulrike A1 - Jarvik, Gail P AB -

Although ~ 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.

ER - TY - JOUR T1 - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. JF - Nat Genet Y1 - 2018 A1 - Mahajan, Anubha A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Zhao, Wei A1 - Robertson, Neil R A1 - Chu, Audrey Y A1 - Gan, Wei A1 - Kitajima, Hidetoshi A1 - Taliun, Daniel A1 - Rayner, N William A1 - Guo, Xiuqing A1 - Lu, Yingchang A1 - Li, Man A1 - Jensen, Richard A A1 - Hu, Yao A1 - Huo, Shaofeng A1 - Lohman, Kurt K A1 - Zhang, Weihua A1 - Cook, James P A1 - Prins, Bram Peter A1 - Flannick, Jason A1 - Grarup, Niels A1 - Trubetskoy, Vassily Vladimirovich A1 - Kravic, Jasmina A1 - Kim, Young Jin A1 - Rybin, Denis V A1 - Yaghootkar, Hanieh A1 - Müller-Nurasyid, Martina A1 - Meidtner, Karina A1 - Li-Gao, Ruifang A1 - Varga, Tibor V A1 - Marten, Jonathan A1 - Li, Jin A1 - Smith, Albert Vernon A1 - An, Ping A1 - Ligthart, Symen A1 - Gustafsson, Stefan A1 - Malerba, Giovanni A1 - Demirkan, Ayse A1 - Tajes, Juan Fernandez A1 - Steinthorsdottir, Valgerdur A1 - Wuttke, Matthias A1 - Lecoeur, Cécile A1 - Preuss, Michael A1 - Bielak, Lawrence F A1 - Graff, Marielisa A1 - Highland, Heather M A1 - Justice, Anne E A1 - Liu, Dajiang J A1 - Marouli, Eirini A1 - Peloso, Gina Marie A1 - Warren, Helen R A1 - Afaq, Saima A1 - Afzal, Shoaib A1 - Ahlqvist, Emma A1 - Almgren, Peter A1 - Amin, Najaf A1 - Bang, Lia B A1 - Bertoni, Alain G A1 - Bombieri, Cristina A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Burtt, Noel P A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Cho, Yoon Shin A1 - Christensen, Cramer A1 - Eastwood, Sophie V A1 - Eckardt, Kai-Uwe A1 - Fischer, Krista A1 - Gambaro, Giovanni A1 - Giedraitis, Vilmantas A1 - Grove, Megan L A1 - de Haan, Hugoline G A1 - Hackinger, Sophie A1 - Hai, Yang A1 - Han, Sohee A1 - Tybjærg-Hansen, Anne A1 - Hivert, Marie-France A1 - Isomaa, Bo A1 - Jäger, Susanne A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Käräjämäki, AnneMari A1 - Kim, Bong-Jo A1 - Kim, Sung Soo A1 - Koistinen, Heikki A A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Jung-Jin A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Lin, Keng-Hung A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jun A1 - Loh, Marie A1 - Mägi, Reedik A1 - Mamakou, Vasiliki A1 - McKean-Cowdin, Roberta A1 - Nadkarni, Girish A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Ntalla, Ioanna A1 - Peyser, Patricia A A1 - Rathmann, Wolfgang A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rode, Line A1 - Rolandsson, Olov A1 - Schönherr, Sebastian A1 - Selvin, Elizabeth A1 - Small, Kerrin S A1 - Stančáková, Alena A1 - Surendran, Praveen A1 - Taylor, Kent D A1 - Teslovich, Tanya M A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tin, Adrienne A1 - Tönjes, Anke A1 - Varbo, Anette A1 - Witte, Daniel R A1 - Wood, Andrew R A1 - Yajnik, Pranav A1 - Yao, Jie A1 - Yengo, Loic A1 - Young, Robin A1 - Amouyel, Philippe A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Chowdhury, Rajiv A1 - Collins, Francis S A1 - Dedoussis, George A1 - Dehghan, Abbas A1 - Deloukas, Panos A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Florez, Jose C A1 - Frossard, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Howson, Joanna M M A1 - Ingelsson, Martin A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lindgren, Cecilia M A1 - Männistö, Satu A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Moitry, Marie A1 - Morris, Andrew D A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Orho-Melander, Marju A1 - Owen, Katharine R A1 - Perola, Markus A1 - Peters, Annette A1 - Province, Michael A A1 - Rasheed, Asif A1 - Ridker, Paul M A1 - Rivadineira, Fernando A1 - Rosendaal, Frits R A1 - Rosengren, Anders H A1 - Salomaa, Veikko A1 - Sheu, Wayne H-H A1 - Sladek, Rob A1 - Smith, Blair H A1 - Strauch, Konstantin A1 - Uitterlinden, André G A1 - Varma, Rohit A1 - Willer, Cristen J A1 - Blüher, Matthias A1 - Butterworth, Adam S A1 - Chambers, John Campbell A1 - Chasman, Daniel I A1 - Danesh, John A1 - van Duijn, Cornelia A1 - Dupuis, Josée A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Grallert, Harald A1 - Groop, Leif A1 - Han, Bok-Ghee A1 - Hansen, Torben A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal Singh A1 - Köttgen, Anna A1 - Kuulasmaa, Kari A1 - Laakso, Markku A1 - Lin, Xu A1 - Lind, Lars A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Marchini, Jonathan A1 - Metspalu, Andres A1 - Mook-Kanamori, Dennis A1 - Nordestgaard, Børge G A1 - Palmer, Colin N A A1 - Pankow, James S A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Rauramaa, Rainer A1 - Sattar, Naveed A1 - Schulze, Matthias B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Thorsteinsdottir, Unnur A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Zeggini, Eleftheria A1 - Scott, Robert A A1 - Barroso, Inês A1 - Frayling, Timothy M A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Boehnke, Michael A1 - Saleheen, Danish A1 - Morris, Andrew P A1 - Rotter, Jerome I A1 - McCarthy, Mark I AB -

We 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.

VL - 50 IS - 4 ER - TY - JOUR T1 - The relation between thyroid function and anemia: a pooled analysis of individual participant data. JF - J Clin Endocrinol Metab Y1 - 2018 A1 - Wopereis, Daisy M A1 - Du Puy, Robert S A1 - van Heemst, Diana A1 - Walsh, John P A1 - Bremner, Alexandra A1 - Bakker, Stephan J L A1 - Bauer, Douglas C A1 - Cappola, Anne R A1 - Ceresini, Graziano A1 - Degryse, Jean A1 - Dullaart, Robin P F A1 - Feller, Martin A1 - Ferrucci, Luigi A1 - Floriani, Carmen A1 - Franco, Oscar H A1 - Iacoviello, Massimo A1 - Iervasi, Georgio A1 - Imaizumi, Misa A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Luben, Robert N A1 - Molinaro, Sabrina A1 - Nauck, Matthias A1 - Patel, Kushang V A1 - Peeters, Robin P A1 - Psaty, Bruce M A1 - Razvi, Salman A1 - Schindhelm, Roger K A1 - van Schoor, Natasja M A1 - Stott, David J A1 - Vaes, Bert A1 - Vanderpump, Mark P J A1 - Völzke, Henry A1 - Westendorp, Rudi G J A1 - Rodondi, Nicolas A1 - Cobbaert, Christa M A1 - Gussekloo, Jacobijn A1 - den Elzen, Wendy P J AB -

Context: 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.

ER - TY - JOUR T1 - Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium. JF - Am J Kidney Dis Y1 - 2018 A1 - Inker, Lesley A A1 - Grams, Morgan E A1 - Levey, Andrew S A1 - Coresh, Josef A1 - Cirillo, Massimo A1 - Collins, John F A1 - Gansevoort, Ron T A1 - Gutierrez, Orlando M A1 - Hamano, Takayuki A1 - Heine, Gunnar H A1 - Ishikawa, Shizukiyo A1 - Jee, Sun Ha A1 - Kronenberg, Florian A1 - Landray, Martin J A1 - Miura, Katsuyuki A1 - Nadkarni, Girish N A1 - Peralta, Carmen A A1 - Rothenbacher, Dietrich A1 - Schaeffner, Elke A1 - Sedaghat, Sanaz A1 - Shlipak, Michael G A1 - Zhang, Luxia A1 - van Zuilen, Arjan D A1 - Hallan, Stein I A1 - Kovesdy, Csaba P A1 - Woodward, Mark A1 - Levin, Adeera AB -

RATIONALE & 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.

ER - TY - JOUR T1 - Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces. JF - J Am Heart Assoc Y1 - 2018 A1 - Nicholson, Christopher J A1 - Singh, Kuldeep A1 - Saphirstein, Robert J A1 - Gao, Yuan Z A1 - Li, Qian A1 - Chiu, Joanna G A1 - Leavis, Paul A1 - Verwoert, Germaine C A1 - Mitchell, G F A1 - Porter, Tyrone A1 - Morgan, Kathleen G AB -

BACKGROUND: 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.

VL - 7 IS - 15 ER - TY - JOUR T1 - Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. JF - Lancet Y1 - 2018 A1 - Wood, Angela M A1 - Kaptoge, Stephen A1 - Butterworth, Adam S A1 - Willeit, Peter A1 - Warnakula, Samantha A1 - Bolton, Thomas A1 - Paige, Ellie A1 - Paul, Dirk S A1 - Sweeting, Michael A1 - Burgess, Stephen A1 - Bell, Steven A1 - Astle, William A1 - Stevens, David A1 - Koulman, Albert A1 - Selmer, Randi M A1 - Verschuren, W M Monique A1 - Sato, Shinichi A1 - Njølstad, Inger A1 - Woodward, Mark A1 - Salomaa, Veikko A1 - Nordestgaard, Børge G A1 - Yeap, Bu B A1 - Fletcher, Astrid A1 - Melander, Olle A1 - Kuller, Lewis H A1 - Balkau, Beverley A1 - Marmot, Michael A1 - Koenig, Wolfgang A1 - Casiglia, Edoardo A1 - Cooper, Cyrus A1 - Arndt, Volker A1 - Franco, Oscar H A1 - Wennberg, Patrik A1 - Gallacher, John A1 - de la Cámara, Agustin Gómez A1 - Völzke, Henry A1 - Dahm, Christina C A1 - Dale, Caroline E A1 - Bergmann, Manuela M A1 - Crespo, Carlos J A1 - van der Schouw, Yvonne T A1 - Kaaks, Rudolf A1 - Simons, Leon A A1 - Lagiou, Pagona A1 - Schoufour, Josje D A1 - Boer, Jolanda M A A1 - Key, Timothy J A1 - Rodriguez, Beatriz A1 - Moreno-Iribas, Conchi A1 - Davidson, Karina W A1 - Taylor, James O A1 - Sacerdote, Carlotta A1 - Wallace, Robert B A1 - Quiros, J Ramon A1 - Tumino, Rosario A1 - Blazer, Dan G A1 - Linneberg, Allan A1 - Daimon, Makoto A1 - Panico, Salvatore A1 - Howard, Barbara A1 - Skeie, Guri A1 - Strandberg, Timo A1 - Weiderpass, Elisabete A1 - Nietert, Paul J A1 - Psaty, Bruce M A1 - Kromhout, Daan A1 - Salamanca-Fernandez, Elena A1 - Kiechl, Stefan A1 - Krumholz, Harlan M A1 - Grioni, Sara A1 - Palli, Domenico A1 - Huerta, José M A1 - Price, Jackie A1 - Sundström, Johan A1 - Arriola, Larraitz A1 - Arima, Hisatomi A1 - Travis, Ruth C A1 - Panagiotakos, Demosthenes B A1 - Karakatsani, Anna A1 - Trichopoulou, Antonia A1 - Kühn, Tilman A1 - Grobbee, Diederick E A1 - Barrett-Connor, Elizabeth A1 - van Schoor, Natasja A1 - Boeing, Heiner A1 - Overvad, Kim A1 - Kauhanen, Jussi A1 - Wareham, Nick A1 - Langenberg, Claudia A1 - Forouhi, Nita A1 - Wennberg, Maria A1 - Després, Jean-Pierre A1 - Cushman, Mary A1 - Cooper, Jackie A A1 - Rodriguez, Carlos J A1 - Sakurai, Masaru A1 - Shaw, Jonathan E A1 - Knuiman, Matthew A1 - Voortman, Trudy A1 - Meisinger, Christa A1 - Tjønneland, Anne A1 - Brenner, Hermann A1 - Palmieri, Luigi A1 - Dallongeville, Jean A1 - Brunner, Eric J A1 - Assmann, Gerd A1 - Trevisan, Maurizio A1 - Gillum, Richard F A1 - Ford, Ian A1 - Sattar, Naveed A1 - Lazo, Mariana A1 - Thompson, Simon G A1 - Ferrari, Pietro A1 - Leon, David A A1 - Smith, George Davey A1 - Peto, Richard A1 - Jackson, Rod A1 - Banks, Emily A1 - Di Angelantonio, Emanuele A1 - Danesh, John AB -

BACKGROUND: 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.

VL - 391 IS - 10129 ER - TY - JOUR T1 - Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction. JF - Circulation Y1 - 2018 A1 - Pandey, Ambarish A1 - Omar, Wally A1 - Ayers, Colby A1 - LaMonte, Michael A1 - Klein, Liviu A1 - Allen, Norrina B A1 - Kuller, Lewis H A1 - Greenland, Philip A1 - Eaton, Charles B A1 - Gottdiener, John S A1 - Lloyd-Jones, Donald M A1 - Berry, Jarett D AB -

BACKGROUND: 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.

VL - 137 IS - 17 ER - TY - JOUR T1 - Sleep characteristics that predict atrial fibrillation. JF - Heart Rhythm Y1 - 2018 A1 - Christensen, Matthew A A1 - Dixit, Shalini A1 - Dewland, Thomas A A1 - Whitman, Isaac R A1 - Nah, Gregory A1 - Vittinghoff, Eric A1 - Mukamal, Kenneth J A1 - Redline, Susan A1 - Robbins, John A A1 - Newman, Anne B A1 - Patel, Sanjay R A1 - Magnani, Jared W A1 - Psaty, Bruce M A1 - Olgin, Jeffrey E A1 - Pletcher, Mark J A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: 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.

VL - 15 IS - 9 ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nat Commun Y1 - 2018 A1 - Davies, Gail A1 - Lam, Max A1 - Harris, Sarah E A1 - Trampush, Joey W A1 - Luciano, Michelle A1 - Hill, W David A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Marioni, Riccardo E A1 - Fawns-Ritchie, Chloe A1 - Liewald, David C M A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Bis, Joshua C A1 - Burdick, Katherine E A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Hayward, Caroline A1 - Hofer, Edith A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Oldmeadow, Christopher A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Petrovic, Katja A1 - Reynolds, Chandra A A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Windham, B Gwen A1 - Wright, Margaret J A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - Attia, John R A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - Bennett, David A A1 - Böhmer, Anne C A1 - Boyle, Patricia A A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Cannon, Tyrone D A1 - Cirulli, Elizabeth T A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Dick, Danielle A1 - Dickinson, Dwight A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Ford, Ian A1 - Freimer, Nelson A A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Griswold, Michael E A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Heiss, Gerardo A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Karlsson, Ida A1 - Kleineidam, Luca A1 - Knopman, David S A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Le Hellard, Stephanie A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Lundervold, Astri J A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Murray, Alison D A1 - Need, Anna C A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - Ollier, William A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poldrack, Russell A A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Riedel-Heller, Steffi G A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Sabb, Fred W A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Scott, Rodney J A1 - Scult, Matthew A A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Stefanis, Nikos C A1 - Stott, David J A1 - Straub, Richard E A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, Andre A1 - Vitart, Veronique A1 - Voineskos, Aristotle N A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Widen, Elisabeth A1 - Yang, Qiong A1 - Zhao, Wei A1 - Adams, Hieab H H A1 - Arking, Dan E A1 - Bilder, Robert M A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - De Jager, Philip L A1 - Debette, Stephanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - Glahn, David C A1 - Hägg, Sara A1 - Hansell, Narelle K A1 - Hariri, Ahmad R A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Keller, Matthew C A1 - Kremen, William S A1 - Launer, Lenore A1 - Lindenberger, Ulman A1 - Palotie, Aarno A1 - Pedersen, Nancy L A1 - Pendleton, Neil A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Raitakari, Olli T A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter W A1 - Schofield, Peter R A1 - Starr, John M A1 - Steen, Vidar M A1 - Trollor, Julian N A1 - Turner, Steven T A1 - van Duijn, Cornelia M A1 - Villringer, Arno A1 - Weinberger, Daniel R A1 - Weir, David R A1 - Wilson, James F A1 - Malhotra, Anil A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Lencz, Todd A1 - Deary, Ian J AB -

General 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Sugar-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. JF - Diabetologia Y1 - 2018 A1 - McKeown, Nicola M A1 - Dashti, Hassan S A1 - Ma, Jiantao A1 - Haslam, Danielle E A1 - Kiefte-de Jong, Jessica C A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Graff, Mariaelisa A1 - Lemaitre, Rozenn N A1 - Rybin, Denis A1 - Sonestedt, Emily A1 - Frazier-Wood, Alexis C A1 - Mook-Kanamori, Dennis O A1 - Li, Yanping A1 - Wang, Carol A A1 - Leermakers, Elisabeth T M A1 - Mikkilä, Vera A1 - Young, Kristin L A1 - Mukamal, Kenneth J A1 - Cupples, L Adrienne A1 - Schulz, Christina-Alexandra A1 - Chen, Tzu-An A1 - Li-Gao, Ruifang A1 - Huang, Tao A1 - Oddy, Wendy H A1 - Raitakari, Olli A1 - Rice, Kenneth A1 - Meigs, James B A1 - Ericson, Ulrika A1 - Steffen, Lyn M A1 - Rosendaal, Frits R A1 - Hofman, Albert A1 - Kähönen, Mika A1 - Psaty, Bruce M A1 - Brunkwall, Louise A1 - Uitterlinden, André G A1 - Viikari, Jorma A1 - Siscovick, David S A1 - Seppälä, Ilkka A1 - North, Kari E A1 - Mozaffarian, Dariush A1 - Dupuis, Josée A1 - Orho-Melander, Marju A1 - Rich, Stephen S A1 - de Mutsert, Renée A1 - Qi, Lu A1 - Pennell, Craig E A1 - Franco, Oscar H A1 - Lehtimäki, Terho A1 - Herman, Mark A AB -

AIMS/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).

VL - 61 IS - 2 ER - TY - JOUR T1 - Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes. JF - J Thromb Haemost Y1 - 2018 A1 - de Haan, H G A1 - van Hylckama Vlieg, A A1 - Lotta, L A A1 - Gorski, Marcin M A1 - Bucciarelli, P A1 - Martinelli, I A1 - Baglin, T P A1 - Peyvandi, F A1 - Rosendaal, F R AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. JF - JACC Heart Fail Y1 - 2018 A1 - Tsao, Connie W A1 - Lyass, Asya A1 - Enserro, Danielle A1 - Larson, Martin G A1 - Ho, Jennifer E A1 - Kizer, Jorge R A1 - Gottdiener, John S A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S AB -

OBJECTIVES: 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.

VL - 6 IS - 8 ER - TY - JOUR T1 - Trajectories of Nonagenarian Health: Gender, Age, and Period Effects. JF - Am J Epidemiol Y1 - 2018 A1 - Odden, Michelle C A1 - Koh, William Jen Hoe A1 - Arnold, Alice M A1 - Rawlings, Andreea M A1 - Psaty, Bruce M A1 - Newman, Anne B AB -

The 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.

ER - TY - JOUR T1 - Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. JF - Int J Obes (Lond) Y1 - 2018 A1 - Gong, J A1 - Nishimura, K K A1 - Fernandez-Rhodes, L A1 - Haessler, J A1 - Bien, S A1 - Graff, M A1 - Lim, U A1 - Lu, Y A1 - Gross, M A1 - Fornage, M A1 - Yoneyama, S A1 - Isasi, C R A1 - Bůžková, P A1 - Daviglus, M A1 - Lin, D-Y A1 - Tao, R A1 - Goodloe, R A1 - Bush, W S A1 - Farber-Eger, E A1 - Boston, J A1 - Dilks, H H A1 - Ehret, G A1 - Gu, C C A1 - Lewis, C E A1 - Nguyen, K-D H A1 - Cooper, R A1 - Leppert, M A1 - Irvin, M R A1 - Bottinger, E P A1 - Wilkens, L R A1 - Haiman, C A A1 - Park, L A1 - Monroe, K R A1 - Cheng, I A1 - Stram, D O A1 - Carlson, C S A1 - Jackson, R A1 - Kuller, L A1 - Houston, D A1 - Kooperberg, C A1 - Buyske, S A1 - Hindorff, L A A1 - Crawford, D C A1 - Loos, R J F A1 - Le Marchand, L A1 - Matise, T C A1 - North, K E A1 - Peters, U AB -

OBJECTIVE: 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.

VL - 42 IS - 3 ER - TY - JOUR T1 - Trans-ethnic Evaluation Identifies Novel Low Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations. JF - J Clin Endocrinol Metab Y1 - 2018 A1 - Hong, Jaeyoung A1 - Hatchell, Kathryn E A1 - Bradfield, Jonathan P A1 - Andrew, Bjonnes A1 - Alessandra, Chesi A1 - Chao-Qiang, Lai A1 - Langefeld, Carl D A1 - Lu, Lingyi A1 - Lu, Yingchang A1 - Lutsey, Pamela L A1 - Musani, Solomon K A1 - Nalls, Mike A A1 - Robinson-Cohen, Cassianne A1 - Roizen, Jeffery D A1 - Saxena, Richa A1 - Tucker, Katherine L A1 - Ziegler, Julie T A1 - Arking, Dan E A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Gilsanz, Vincente A1 - Houston, Denise K A1 - Kalkwarf, Heidi J A1 - Kelly, Andrea A1 - Lappe, Joan M A1 - Liu, Yongmei A1 - Michos, Erin D A1 - Oberfield, Sharon E A1 - Palmer, Nicholette D A1 - Rotter, Jerome I A1 - Sapkota, Bishwa A1 - Shepherd, John A A1 - Wilson, James G A1 - Basu, Saonli A1 - de Boer, Ian H A1 - Divers, Jasmin A1 - Freedman, Barry I A1 - Grant, Struan F A A1 - Hakanarson, Hakon A1 - Harris, Tamara B A1 - Kestenbaum, Bryan R A1 - Kritchevsky, Stephen B A1 - Loos, Ruth J F A1 - Norris, Jill M A1 - Norwood, Arnita F A1 - Ordovas, Jose M A1 - Pankow, James S A1 - Psaty, Bruce M A1 - Sanhgera, Dharambir K A1 - Wagenknecht, Lynne E A1 - Zemel, Babette S A1 - Meigs, James A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Wang, Thomas A1 - Liu, Ching-Ti A1 - Engelman, Corinne D A1 - Billings, Liana K AB -

Context: 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.

ER - TY - JOUR T1 - Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. JF - Mol Psychiatry Y1 - 2018 A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Kunkle, Brian W A1 - Chen, Yuning A1 - Hamilton-Nelson, Kara L A1 - Bush, William S A1 - Salerno, William J A1 - Lancour, Daniel A1 - Ma, Yiyi A1 - Renton, Alan E A1 - Marcora, Edoardo A1 - Farrell, John J A1 - Zhao, Yi A1 - Qu, Liming A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Beecham, Gary W A1 - Below, Jennifer E A1 - Campion, Dominique A1 - Charbonnier, Camille A1 - Chung, Jaeyoon A1 - Crane, Paul K A1 - Cruchaga, Carlos A1 - Cupples, L Adrienne A1 - Dartigues, Jean-François A1 - Debette, Stephanie A1 - Deleuze, Jean-Francois A1 - Fulton, Lucinda A1 - Gabriel, Stacey B A1 - Genin, Emmanuelle A1 - Gibbs, Richard A A1 - Goate, Alison A1 - Grenier-Boley, Benjamin A1 - Gupta, Namrata A1 - Haines, Jonathan L A1 - Havulinna, Aki S A1 - Helisalmi, Seppo A1 - Hiltunen, Mikko A1 - Howrigan, Daniel P A1 - Ikram, M Arfan A1 - Kaprio, Jaakko A1 - Konrad, Jan A1 - Kuzma, Amanda A1 - Lander, Eric S A1 - Lathrop, Mark A1 - Lehtimäki, Terho A1 - Lin, Honghuang A1 - Mattila, Kari A1 - Mayeux, Richard A1 - Muzny, Donna M A1 - Nasser, Waleed A1 - Neale, Benjamin A1 - Nho, Kwangsik A1 - Nicolas, Gaël A1 - Patel, Devanshi A1 - Pericak-Vance, Margaret A A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Quenez, Olivier A1 - Rajabli, Farid A1 - Redon, Richard A1 - Reitz, Christiane A1 - Remes, Anne M A1 - Salomaa, Veikko A1 - Sarnowski, Chloe A1 - Schmidt, Helena A1 - Schmidt, Michael A1 - Schmidt, Reinhold A1 - Soininen, Hilkka A1 - Thornton, Timothy A A1 - Tosto, Giuseppe A1 - Tzourio, Christophe A1 - van der Lee, Sven J A1 - van Duijn, Cornelia M A1 - Vardarajan, Badri A1 - Wang, Weixin A1 - Wijsman, Ellen A1 - Wilson, Richard K A1 - Witten, Daniela A1 - Worley, Kim C A1 - Zhang, Xiaoling A1 - Bellenguez, Céline A1 - Lambert, Jean-Charles A1 - Kurki, Mitja I A1 - Palotie, Aarno A1 - Daly, Mark A1 - Boerwinkle, Eric A1 - Lunetta, Kathryn L A1 - DeStefano, Anita L A1 - Dupuis, Josée A1 - Martin, Eden R A1 - Schellenberg, Gerard D A1 - Seshadri, Sudha A1 - Naj, Adam C A1 - Fornage, Myriam A1 - Farrer, Lindsay A AB -

The 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.

ER - TY - JOUR T1 - Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease. JF - Ann Clin Transl Neurol Y1 - 2018 A1 - Vardarajan, Badri N A1 - Barral, Sandra A1 - Jaworski, James A1 - Beecham, Gary W A1 - Blue, Elizabeth A1 - Tosto, Giuseppe A1 - Reyes-Dumeyer, Dolly A1 - Medrano, Martin A1 - Lantigua, Rafael A1 - Naj, Adam A1 - Thornton, Timothy A1 - DeStefano, Anita A1 - Martin, Eden A1 - Wang, Li-San A1 - Brown, Lisa A1 - Bush, William A1 - van Duijn, Cornelia A1 - Goate, Allison A1 - Farrer, Lindsay A1 - Haines, Jonathan L A1 - Boerwinkle, Eric A1 - Schellenberg, Gerard A1 - Wijsman, Ellen A1 - Pericak-Vance, Margaret A A1 - Mayeux, Richard A1 - Wang, Li-San AB -

Objective: 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.

VL - 5 IS - 4 ER - TY - JOUR T1 - Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. JF - Ann Clin Transl Neurol Y1 - 2018 A1 - Raghavan, Neha S A1 - Brickman, Adam M A1 - Andrews, Howard A1 - Manly, Jennifer J A1 - Schupf, Nicole A1 - Lantigua, Rafael A1 - Wolock, Charles J A1 - Kamalakaran, Sitharthan A1 - Petrovski, Slave A1 - Tosto, Giuseppe A1 - Vardarajan, Badri N A1 - Goldstein, David B A1 - Mayeux, Richard AB -

Objective: 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.

VL - 5 IS - 7 ER - TY - JOUR T1 - Abnormal Fasting Glucose Increases Risk of Unrecognized Myocardial Infarctions in an Elderly Cohort. JF - J Am Geriatr Soc Y1 - 2019 A1 - Stacey, Richard Brandon A1 - Zgibor, Janice A1 - Leaverton, Paul E A1 - Schocken, Douglas D A1 - Peregoy, Jennifer A A1 - Lyles, Mary F A1 - Bertoni, Alain G A1 - Burke, Gregory L AB -

OBJECTIVES: 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.

VL - 67 IS - 1 ER - TY - JOUR T1 - The Accuracy of Cardiovascular Pooled Cohort Risk Estimates in U.S. Older Adults. JF - J Gen Intern Med Y1 - 2019 A1 - Nanna, Michael G A1 - Peterson, Eric D A1 - Wojdyla, Daniel A1 - Navar, Ann Marie AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. JF - Hum Mol Genet Y1 - 2019 A1 - Wang, Heming A1 - Cade, Brian E A1 - Sofer, Tamar A1 - Sands, Scott A A1 - Chen, Han A1 - Browning, Sharon R A1 - Stilp, Adrienne M A1 - Louie, Tin L A1 - Thornton, Timothy A A1 - Johnson, W Craig A1 - Below, Jennifer E A1 - Conomos, Matthew P A1 - Evans, Daniel S A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Wood, Alexis C A1 - Mei, Hao A1 - Yaffe, Kristine A1 - Loredo, Jose S A1 - Ramos, Alberto R A1 - Barrett-Connor, Elizabeth A1 - Ancoli-Israel, Sonia A1 - Zee, Phyllis C A1 - Arens, Raanan A1 - Shah, Neomi A A1 - Taylor, Kent D A1 - Tranah, Gregory J A1 - Stone, Katie L A1 - Hanis, Craig L A1 - Wilson, James G A1 - Gottlieb, Daniel J A1 - Patel, Sanjay R A1 - Rice, Ken A1 - Post, Wendy S A1 - Rotter, Jerome I A1 - Sunyaev, Shamil R A1 - Cai, Jianwen A1 - Lin, Xihong A1 - Purcell, Shaun M A1 - Laurie, Cathy C A1 - Saxena, Richa A1 - Redline, Susan A1 - Zhu, Xiaofeng AB -

Obstructive 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.

VL - 28 IS - 4 ER - TY - JOUR T1 - APOL1 gene variants and kidney disease in whites: the cardiovascular health study. JF - Nephrol Dial Transplant Y1 - 2019 A1 - Drury, Erika R A1 - Friedman, David J A1 - Pollak, Martin R A1 - Ix, Joachim H A1 - Kuller, Lewis H A1 - Tracy, Russell P A1 - Mukamal, Kenneth J VL - 34 IS - 12 ER - TY - JOUR T1 - Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study. JF - JAMA Cardiol Y1 - 2019 A1 - Ellervik, Christina A1 - Roselli, Carolina A1 - Christophersen, Ingrid E A1 - Alonso, Alvaro A1 - Pietzner, Maik A1 - Sitlani, Collen M A1 - Trompet, Stella A1 - Arking, Dan E A1 - Geelhoed, Bastiaan A1 - Guo, Xiuqing A1 - Kleber, Marcus E A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Macfarlane, Peter A1 - Selvin, Elizabeth A1 - Shaffer, Christian A1 - Smith, Albert V A1 - Verweij, Niek A1 - Weiss, Stefan A1 - Cappola, Anne R A1 - Dörr, Marcus A1 - Gudnason, Vilmundur A1 - Heckbert, Susan A1 - Mooijaart, Simon A1 - März, Winfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Roden, Dan A1 - Stott, David J A1 - Völzke, Henry A1 - Benjamin, Emelia J A1 - Delgado, Graciela A1 - Ellinor, Patrick A1 - Homuth, Georg A1 - Köttgen, Anna A1 - Jukema, Johan W A1 - Lubitz, Steven A A1 - Mora, Samia A1 - Rienstra, Michiel A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - van der Harst, Pim A1 - Albert, Christine M A1 - Chasman, Daniel I AB -

Importance: 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.

ER - TY - JOUR T1 - The association between physical function and proximity to death in older adults: a multilevel analysis of 4,150 decedents from the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 2019 A1 - Karunananthan, Sathya A1 - Moodie, Erica E M A1 - Bergman, Howard A1 - Payette, Hélène A1 - Wolfson, David A1 - Diehr, Paula H A1 - Wolfson, Christina AB -

PURPOSE: 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.

VL - 35 ER - TY - JOUR T1 - {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 individuals JF - Am J Clin Nutr Y1 - 2019 A1 - Mandaviya, P. R. A1 - Joehanes, R. A1 - Brody, J. A1 - Castillo-Fernandez, J. E. A1 - Dekkers, K. F. A1 - Do, A. N. A1 - Graff, M. A1 - H?nninen, I. K. A1 - Tanaka, T. A1 - de Jonge, E. A. L. A1 - Kiefte-de Jong, J. C. A1 - Absher, D. M. A1 - Aslibekyan, S. A1 - de Rijke, Y. B. A1 - Fornage, M. A1 - Hernandez, D. G. A1 - Hurme, M. A. A1 - Ikram, M. A. A1 - Jacques, P. F. A1 - Justice, A. E. A1 - Kiel, D. P. A1 - Lemaitre, R. N. A1 - Mendelson, M. M. A1 - Mikkil?, V. A1 - Moore, A. Z. A1 - Pallister, T. A1 - Raitakari, O. T. A1 - Schalkwijk, C. G. A1 - Sha, J. A1 - Slagboom, E. P. E. A1 - Smith, C. E. A1 - Stehouwer, C. D. A. A1 - Tsai, P. C. A1 - Uitterlinden, A. G. A1 - van der Kallen, C. J. H. A1 - van Heemst, D. A1 - Arnett, D. K. A1 - Bandinelli, S. A1 - Bell, J. T. A1 - Heijmans, B. T. A1 - Lehtim?ki, T. A1 - Levy, D. A1 - North, K. E. A1 - Sotoodehnia, N. A1 - van Greevenbroek, M. M. J. A1 - van Meurs, J. B. J. A1 - Heil, S. G. AB - Folate 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. VL - 110 ER - TY - JOUR T1 - Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. JF - Brain Y1 - 2019 A1 - Mishra, Aniket A1 - Chauhan, Ganesh A1 - Violleau, Marie-Helene A1 - Vojinovic, Dina A1 - Jian, Xueqiu A1 - Bis, Joshua C A1 - Li, Shuo A1 - Saba, Yasaman A1 - Grenier-Boley, Benjamin A1 - Yang, Qiong A1 - Bartz, Traci M A1 - Hofer, Edith A1 - Soumaré, Aïcha A1 - Peng, Fen A1 - Duperron, Marie-Gabrielle A1 - Foglio, Mario A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Psaty, Bruce M A1 - Launer, Lenore J A1 - Boerwinkle, Eric A1 - Zhu, Yicheng A1 - Mazoyer, Bernard A1 - Lathrop, Mark A1 - Bellenguez, Céline A1 - van Duijn, Cornelia M A1 - Ikram, M Arfan A1 - Schmidt, Helena A1 - Longstreth, W T A1 - Fornage, Myriam A1 - Seshadri, Sudha A1 - Joutel, Anne A1 - Tzourio, Christophe A1 - Debette, Stephanie AB -

We 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.

ER - TY - JOUR T1 - Associations of autozygosity with a broad range of human phenotypes. JF - Nat Commun Y1 - 2019 A1 - Clark, David W A1 - Okada, Yukinori A1 - Moore, Kristjan H S A1 - Mason, Dan A1 - Pirastu, Nicola A1 - Gandin, Ilaria A1 - Mattsson, Hannele A1 - Barnes, Catriona L K A1 - Lin, Kuang A1 - Zhao, Jing Hua A1 - Deelen, Patrick A1 - Rohde, Rebecca A1 - Schurmann, Claudia A1 - Guo, Xiuqing A1 - Giulianini, Franco A1 - Zhang, Weihua A1 - Medina-Gómez, Carolina A1 - Karlsson, Robert A1 - Bao, Yanchun A1 - Bartz, Traci M A1 - Baumbach, Clemens A1 - Biino, Ginevra A1 - Bixley, Matthew J A1 - Brumat, Marco A1 - Chai, Jin-Fang A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Dekker, Annelot M A1 - Eccles, David A A1 - van Eijk, Kristel R A1 - Fuchsberger, Christian A1 - Gao, He A1 - Germain, Marine A1 - Gordon, Scott D A1 - de Haan, Hugoline G A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Huerta-Chagoya, Alicia A1 - Igartua, Catherine A1 - Jansen, Iris E A1 - Jia, Yucheng A1 - Kacprowski, Tim A1 - Karlsson, Torgny A1 - Kleber, Marcus E A1 - Li, Shengchao Alfred A1 - Li-Gao, Ruifang A1 - Mahajan, Anubha A1 - Matsuda, Koichi A1 - Meidtner, Karina A1 - Meng, Weihua A1 - Montasser, May E A1 - van der Most, Peter J A1 - Munz, Matthias A1 - Nutile, Teresa A1 - Palviainen, Teemu A1 - Prasad, Gauri A1 - Prasad, Rashmi B A1 - Priyanka, Tallapragada Divya Sri A1 - Rizzi, Federica A1 - Salvi, Erika A1 - Sapkota, Bishwa R A1 - Shriner, Daniel A1 - Skotte, Line A1 - Smart, Melissa C A1 - Smith, Albert Vernon A1 - van der Spek, Ashley A1 - Spracklen, Cassandra N A1 - Strawbridge, Rona J A1 - Tajuddin, Salman M A1 - Trompet, Stella A1 - Turman, Constance A1 - Verweij, Niek A1 - Viberti, Clara A1 - Wang, Lihua A1 - Warren, Helen R A1 - Wootton, Robyn E A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yousri, Noha A A1 - Zhao, Wei A1 - Adeyemo, Adebowale A A1 - Afaq, Saima A1 - Aguilar-Salinas, Carlos Alberto A1 - Akiyama, Masato A1 - Albert, Matthew L A1 - Allison, Matthew A A1 - Alver, Maris A1 - Aung, Tin A1 - Azizi, Fereidoun A1 - Bentley, Amy R A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Borja, Judith B A1 - de Borst, Gert J A1 - Bottinger, Erwin P A1 - Broer, Linda A1 - Campbell, Harry A1 - Chanock, Stephen A1 - Chee, Miao-Li A1 - Chen, Guanjie A1 - Chen, Yii-der I A1 - Chen, Zhengming A1 - Chiu, Yen-Feng A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Concas, Maria Pina A1 - Corley, Janie A1 - Cugliari, Giovanni A1 - van Dam, Rob M A1 - Damulina, Anna A1 - Daneshpour, Maryam S A1 - Day, Felix R A1 - Delgado, Graciela E A1 - Dhana, Klodian A1 - Doney, Alexander S F A1 - Dörr, Marcus A1 - Doumatey, Ayo P A1 - Dzimiri, Nduna A1 - Ebenesersdóttir, S Sunna A1 - Elliott, Joshua A1 - Elliott, Paul A1 - Ewert, Ralf A1 - Felix, Janine F A1 - Fischer, Krista A1 - Freedman, Barry I A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gögele, Martin A1 - Goodarzi, Mark O A1 - Graff, Mariaelisa A1 - Granot-Hershkovitz, Einat A1 - Grodstein, Francine A1 - Guarrera, Simonetta A1 - Gudbjartsson, Daniel F A1 - Guity, Kamran A1 - Gunnarsson, Bjarni A1 - Guo, Yu A1 - Hagenaars, Saskia P A1 - Haiman, Christopher A A1 - Halevy, Avner A1 - Harris, Tamara B A1 - Hedayati, Mehdi A1 - van Heel, David A A1 - Hirata, Makoto A1 - Höfer, Imo A1 - Hsiung, Chao Agnes A1 - Huang, Jinyan A1 - Hung, Yi-Jen A1 - Ikram, M Arfan A1 - Jagadeesan, Anuradha A1 - Jousilahti, Pekka A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerrison, Nicola D A1 - Kessler, Thorsten A1 - Khaw, Kay-Tee A1 - Khor, Chiea Chuen A1 - de Kleijn, Dominique P V A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Krämer, Bernhard K A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lawlor, Deborah A A1 - Lee, I-Te A1 - Lee, Wen-Jane A1 - Lerch, Markus M A1 - Li, Liming A1 - Liu, Jianjun A1 - Loh, Marie A1 - London, Stephanie J A1 - Loomis, Stephanie A1 - Lu, Yingchang A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - Manunta, Paolo A1 - Másson, Gísli A1 - Matoba, Nana A1 - Mei, Xue W A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Mezzavilla, Massimo A1 - Milani, Lili A1 - Millwood, Iona Y A1 - Momozawa, Yukihide A1 - Moore, Amy A1 - Morange, Pierre-Emmanuel A1 - Moreno-Macias, Hortensia A1 - Mori, Trevor A A1 - Morrison, Alanna C A1 - Muka, Taulant A1 - Murakami, Yoshinori A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Mychaleckyj, Josyf C A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Neville, Matt J A1 - Nolte, Ilja M A1 - Ong, Ken K A1 - Orozco, Lorena A1 - Padmanabhan, Sandosh A1 - Pálsson, Gunnar A1 - Pankow, James S A1 - Pattaro, Cristian A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Quintana-Murci, Lluis A1 - Räikkönen, Katri A1 - Ralhan, Sarju A1 - Rao, Dabeeru C A1 - van Rheenen, Wouter A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rietveld, Cornelius A A1 - Robino, Antonietta A1 - van Rooij, Frank J A A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Sabater-Lleal, Maria A1 - Sala, Cinzia Felicita A1 - Salomaa, Veikko A1 - Sandow, Kevin A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sedaghati-Khayat, Bahareh A1 - Sennblad, Bengt A1 - van Setten, Jessica A1 - Sever, Peter J A1 - Sheu, Wayne H-H A1 - Shi, Yuan A1 - Shrestha, Smeeta A1 - Shukla, Sharvari Rahul A1 - Sigurdsson, Jon K A1 - Sikka, Timo Tonis A1 - Singh, Jai Rup A1 - Smith, Blair H A1 - Stančáková, Alena A1 - Stanton, Alice A1 - Starr, John M A1 - Stefansdottir, Lilja A1 - Straker, Leon A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Swertz, Morris A A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Terzikhan, Natalie A1 - Tham, Yih-Chung A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tillander, Annika A1 - Tracy, Russell P A1 - Tusié-Luna, Teresa A1 - Tzoulaki, Ioanna A1 - Vaccargiu, Simona A1 - Vangipurapu, Jagadish A1 - Veldink, Jan H A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vuoksimaa, Eero A1 - Wakil, Salma M A1 - Waldenberger, Melanie A1 - Wander, Gurpreet S A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Wild, Sarah A1 - Yajnik, Chittaranjan S A1 - Yuan, Jian-Min A1 - Zeng, Lingyao A1 - Zhang, Liang A1 - Zhou, Jie A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Becker, Diane M A1 - Lehne, Benjamin A1 - Bennett, David A A1 - van den Berg, Leonard H A1 - Berndt, Sonja I A1 - Bharadwaj, Dwaipayan A1 - Bielak, Lawrence F A1 - Bochud, Murielle A1 - Boehnke, Mike A1 - Bouchard, Claude A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carmi, Shai A1 - Caulfield, Mark J A1 - Cesarini, David A1 - Chambers, John C A1 - Chandak, Giriraj Ratan A1 - Cheng, Ching-Yu A1 - Ciullo, Marina A1 - Cornelis, Marilyn A1 - Cusi, Daniele A1 - Smith, George Davey A1 - Deary, Ian J A1 - Dorajoo, Rajkumar A1 - van Duijn, Cornelia M A1 - Ellinghaus, David A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Evans, Michele K A1 - Faul, Jessica D A1 - Feenstra, Bjarke A1 - Feitosa, Mary A1 - Foisy, Sylvain A1 - Franke, Andre A1 - Friedlander, Yechiel A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Gonzalez, Clicerio A1 - Goyette, Philippe A1 - Grant, Struan F A A1 - Griffiths, Lyn R A1 - Groop, Leif A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hakonarson, Hakon A1 - Hamsten, Anders A1 - van der Harst, Pim A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hochner, Hagit A1 - Huikuri, Heikki A1 - Hunt, Steven C A1 - Jaddoe, Vincent W V A1 - De Jager, Philip L A1 - Johannesson, Magnus A1 - Johansson, Asa A1 - Jonas, Jost B A1 - Jukema, J Wouter A1 - Junttila, Juhani A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kumari, Meena A1 - Laakso, Markku A1 - van der Laan, Sander W A1 - Lahti, Jari A1 - Laudes, Matthias A1 - Lea, Rodney A A1 - Lieb, Wolfgang A1 - Lumley, Thomas A1 - Martin, Nicholas G A1 - März, Winfried A1 - Matullo, Giuseppe A1 - McCarthy, Mark I A1 - Medland, Sarah E A1 - Merriman, Tony R A1 - Metspalu, Andres A1 - Meyer, Brian F A1 - Mohlke, Karen L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis A1 - Munroe, Patricia B A1 - North, Kari E A1 - Nyholt, Dale R A1 - O'Connell, Jeffery R A1 - Ober, Carole A1 - Oldehinkel, Albertine J A1 - Palmas, Walter A1 - Palmer, Colin A1 - Pasterkamp, Gerard G A1 - Patin, Etienne A1 - Pennell, Craig E A1 - Perusse, Louis A1 - Peyser, Patricia A A1 - Pirastu, Mario A1 - Polderman, Tinca J C A1 - Porteous, David J A1 - Posthuma, Danielle A1 - Psaty, Bruce M A1 - Rioux, John D A1 - Rivadeneira, Fernando A1 - Rotimi, Charles A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - den Ruijter, Hester M A1 - Sanghera, Dharambir K A1 - Sattar, Naveed A1 - Schmidt, Reinhold A1 - Schulze, Matthias B A1 - Schunkert, Heribert A1 - Scott, Robert A A1 - Shuldiner, Alan R A1 - Sim, Xueling A1 - Small, Neil A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Tai, E-Shyong A1 - Teumer, Alexander A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Trégouët, David-Alexandre A1 - Tuomi, Tiinamaija A1 - Vollenweider, Peter A1 - Wang, Carol A A1 - Weir, David R A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wong, Tien-Yin A1 - Wright, John A1 - Yang, Jingyun A1 - Yu, Lei A1 - Zemel, Babette S A1 - Zonderman, Alan B A1 - Perola, Markus A1 - Magnusson, Patrik K E A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Chasman, Daniel I A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Franke, Lude A1 - Haley, Chris S A1 - Hayward, Caroline A1 - Walters, Robin G A1 - Perry, John R B A1 - Esko, Tõnu A1 - Helgason, Agnar A1 - Stefansson, Kari A1 - Joshi, Peter K A1 - Kubo, Michiaki A1 - Wilson, James F AB -

In 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.

VL - 10 IS - 1 ER - TY - JOUR T1 - Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. JF - PLoS Genet Y1 - 2019 A1 - Cade, Brian E A1 - Chen, Han A1 - Stilp, Adrienne M A1 - Louie, Tin A1 - Ancoli-Israel, Sonia A1 - Arens, Raanan A1 - Barfield, Richard A1 - Below, Jennifer E A1 - Cai, Jianwen A1 - Conomos, Matthew P A1 - Evans, Daniel S A1 - Frazier-Wood, Alexis C A1 - Gharib, Sina A A1 - Gleason, Kevin J A1 - Gottlieb, Daniel J A1 - Hillman, David R A1 - Johnson, W Craig A1 - Lederer, David J A1 - Lee, Jiwon A1 - Loredo, Jose S A1 - Mei, Hao A1 - Mukherjee, Sutapa A1 - Patel, Sanjay R A1 - Post, Wendy S A1 - Purcell, Shaun M A1 - Ramos, Alberto R A1 - Reid, Kathryn J A1 - Rice, Ken A1 - Shah, Neomi A A1 - Sofer, Tamar A1 - Taylor, Kent D A1 - Thornton, Timothy A A1 - Wang, Heming A1 - Yaffe, Kristine A1 - Zee, Phyllis C A1 - Hanis, Craig L A1 - Palmer, Lyle J A1 - Rotter, Jerome I A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Wilson, James G A1 - Sunyaev, Shamil R A1 - Laurie, Cathy C A1 - Zhu, Xiaofeng A1 - Saxena, Richa A1 - Lin, Xihong A1 - Redline, Susan KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cell Adhesion Molecules, Neuronal KW - Computational Biology KW - Extracellular Matrix Proteins KW - Female KW - Gene Regulatory Networks KW - Genetic Variation KW - Genome-Wide Association Study KW - Hexokinase KW - Humans KW - Hypoxia KW - Interleukin-18 Receptor alpha Subunit KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - NLR Family, Pyrin Domain-Containing 3 Protein KW - Oxygen KW - Oxyhemoglobins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Serine Endopeptidases KW - Sleep KW - Sleep Apnea Syndromes KW - Young Adult AB -

Sleep 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.

VL - 15 IS - 4 ER - TY - JOUR T1 - Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality. JF - Circulation Y1 - 2019 A1 - Marklund, Matti A1 - Wu, Jason H Y A1 - Imamura, Fumiaki A1 - Del Gobbo, Liana C A1 - Fretts, Amanda A1 - de Goede, Janette A1 - Shi, Peilin A1 - Tintle, Nathan A1 - Wennberg, Maria A1 - Aslibekyan, Stella A1 - Chen, Tzu-An A1 - de Oliveira Otto, Marcia C A1 - Hirakawa, Yoichiro A1 - Eriksen, Helle Højmark A1 - Kröger, Janine A1 - Laguzzi, Federica A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Prem, Kiesha A1 - Samieri, Cecilia A1 - Virtanen, Jyrki A1 - Wood, Alexis C A1 - Wong, Kerry A1 - Yang, Wei-Sin A1 - Zhou, Xia A1 - Baylin, Ana A1 - Boer, Jolanda M A A1 - Brouwer, Ingeborg A A1 - Campos, Hannia A1 - Chaves, Paulo H M A1 - Chien, Kuo-Liong A1 - de Faire, Ulf A1 - Djoussé, Luc A1 - Eiriksdottir, Gudny A1 - El-Abbadi, Naglaa A1 - Forouhi, Nita G A1 - Michael Gaziano, J A1 - Geleijnse, Johanna M A1 - Gigante, Bruna A1 - Giles, Graham A1 - Guallar, Eliseo A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Harris, William S A1 - Helmer, Catherine A1 - Hellenius, Mai-Lis A1 - Hodge, Allison A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Jansson, Jan-Håkan A1 - Kalsbeek, Anya A1 - Khaw, Kay-Tee A1 - Koh, Woon-Puay A1 - Laakso, Markku A1 - Leander, Karin A1 - Lin, Hung-Ju A1 - Lind, Lars A1 - Luben, Robert A1 - Luo, Juhua A1 - McKnight, Barbara A1 - Mursu, Jaakko A1 - Ninomiya, Toshiharu A1 - Overvad, Kim A1 - Psaty, Bruce M A1 - Rimm, Eric A1 - Schulze, Matthias B A1 - Siscovick, David A1 - Skjelbo Nielsen, Michael A1 - Smith, Albert V A1 - Steffen, Brian T A1 - Steffen, Lyn A1 - Sun, Qi A1 - Sundström, Johan A1 - Tsai, Michael Y A1 - Tunstall-Pedoe, Hugh A1 - Uusitupa, Matti I J A1 - van Dam, Rob M A1 - Veenstra, Jenna A1 - Monique Verschuren, W M A1 - Wareham, Nick A1 - Willett, Walter A1 - Woodward, Mark A1 - Yuan, Jian-Min A1 - Micha, Renata A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush A1 - Riserus, Ulf AB -

BACKGROUND: 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.

VL - 139 IS - 21 ER - TY - JOUR T1 - Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. JF - Circulation Y1 - 2019 A1 - Agha, Golareh A1 - Mendelson, Michael M A1 - Ward-Caviness, Cavin K A1 - Joehanes, Roby A1 - Huan, Tianxiao A1 - Gondalia, Rahul A1 - Salfati, Elias A1 - Brody, Jennifer A A1 - Fiorito, Giovanni A1 - Bressler, Jan A1 - Chen, Brian H A1 - Ligthart, Symen A1 - Guarrera, Simonetta A1 - Colicino, Elena A1 - Just, Allan C A1 - Wahl, Simone A1 - Gieger, Christian A1 - Vandiver, Amy R A1 - Tanaka, Toshiko A1 - Hernandez, Dena G A1 - Pilling, Luke C A1 - Singleton, Andrew B A1 - Sacerdote, Carlotta A1 - Krogh, Vittorio A1 - Panico, Salvatore A1 - Tumino, Rosario A1 - Li, Yun A1 - Zhang, Guosheng A1 - Stewart, James D A1 - Floyd, James S A1 - Wiggins, Kerri L A1 - Rotter, Jerome I A1 - Multhaup, Michael A1 - Bakulski, Kelly A1 - Horvath, Steven A1 - Tsao, Philip S A1 - Absher, Devin M A1 - Vokonas, Pantel A1 - Hirschhorn, Joel A1 - Fallin, M Daniele A1 - Liu, Chunyu A1 - Bandinelli, Stefania A1 - Boerwinkle, Eric A1 - Dehghan, Abbas A1 - Schwartz, Joel D A1 - Psaty, Bruce M A1 - Feinberg, Andrew P A1 - Hou, Lifang A1 - Ferrucci, Luigi A1 - Sotoodehnia, Nona A1 - Matullo, Giuseppe A1 - Peters, Annette A1 - Fornage, Myriam A1 - Assimes, Themistocles L A1 - Whitsel, Eric A A1 - Levy, Daniel A1 - Baccarelli, Andrea A KW - Adult KW - Aged KW - Cohort Studies KW - Coronary Disease KW - CpG Islands KW - DNA Methylation KW - Europe KW - Female KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Leukocytes KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Population Groups KW - Prognosis KW - Prospective Studies KW - Risk KW - United States AB -

BACKGROUND: 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.

VL - 140 IS - 8 ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

Chronic 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.

VL - 51 IS - 6 ER - TY - JOUR T1 - Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation. JF - Circ Genom Precis Med Y1 - 2019 A1 - Dörr, Marcus A1 - Hamburg, Naomi M A1 - Müller, Christian A1 - Smith, Nicholas L A1 - Gustafsson, Stefan A1 - Lehtimäki, Terho A1 - Teumer, Alexander A1 - Zeller, Tanja A1 - Li, Xiaohui A1 - Lind, Lars A1 - Raitakari, Olli T A1 - Völker, Uwe A1 - Blankenberg, Stefan A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Kähönen, Mika A1 - Lemaitre, Rozenn N A1 - Wild, Philipp S A1 - Nauck, Matthias A1 - Völzke, Henry A1 - Münzel, Thomas A1 - Mitchell, Gary F A1 - Psaty, Bruce M A1 - Lindgren, Cecilia M A1 - Larson, Martin G A1 - Felix, Stephan B A1 - Ingelsson, Erik A1 - Lyytikäinen, Leo-Pekka A1 - Herrington, David A1 - Benjamin, Emelia J A1 - Schnabel, Renate B VL - 12 IS - 2 ER - TY - JOUR T1 - Disentangling the genetics of lean mass. JF - Am J Clin Nutr Y1 - 2019 A1 - Karasik, David A1 - Zillikens, M Carola A1 - Hsu, Yi-Hsiang A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Bochud, Murielle A1 - Borecki, Ingrid B A1 - Broer, Linda A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos-Obando, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Chambers, John C A1 - Chen, Zhao A1 - Cho, Nam H A1 - Choi, Hyung Jin A1 - Chou, Wen-Chi A1 - Cummings, Steven R A1 - de Groot, Lisette C P G M A1 - De Jager, Phillip L A1 - Demuth, Ilja A1 - Diatchenko, Luda A1 - Econs, Michael J A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Eriksson, Joel A1 - Eriksson, Johan G A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Gieger, Christian A1 - Grallert, Harald A1 - Gudnason, Vilmundur A1 - Lenore, Launer J A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Johnson, Toby A1 - Biffar, Reiner A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koller, Daniel L A1 - Kooner, Jaspal S A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kutalik, Zoltán A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lill, Christina A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Livshits, Gregory A1 - Ljunggren, Osten A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Luan, Jian'an A1 - Luben, Robert N A1 - Malkin, Ida A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Nethander, Maria A1 - Newman, Anne B A1 - O'Connell, Jeffery R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Prince, Richard L A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schipf, Sabine A1 - Shin, Chan Soo A1 - Smith, Albert V A1 - Smith, Shad B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stančáková, Alena A1 - Stefansson, Kari A1 - Steinhagen-Thiessen, Elisabeth A1 - Stolk, Lisette A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - Vandenput, Liesbeth A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - J Wareham, Nicholas A1 - Waterworth, Dawn A1 - Weedon, Michael N A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Yerges-Armstrong, Laura M A1 - Yu, Lei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhou, Yanhua A1 - Nielson, Carrie M A1 - Harris, Tamara B A1 - Demissie, Serkalem A1 - Kiel, Douglas P A1 - Ohlsson, Claes AB -

Background: 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.

VL - 109 IS - 2 ER - TY - JOUR T1 - Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations. JF - Sleep Y1 - 2019 A1 - Barfield, Richard A1 - Wang, Heming A1 - Liu, Yongmei A1 - Brody, Jennifer A A1 - Swenson, Brenton A1 - Li, Ruitong A1 - Bartz, Traci M A1 - Sotoodehnia, Nona A1 - Chen, Yii-der I A1 - Cade, Brian E A1 - Chen, Han A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Gharib, Sina A A1 - Johnson, W Craig A1 - Rotter, Jerome I A1 - Saxena, Richa A1 - Purcell, Shaun A1 - Lin, Xihong A1 - Redline, Susan A1 - Sofer, Tamar AB -

STUDY 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.

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A1 - Thompson, S. G. A1 - Danesh, J. A1 - Di Angelantonio, E. A1 - Tipping, R. W. A1 - Simpson, L. M. A1 - Pressel, S. L. A1 - Couper, D. J. A1 - Nambi, V. A1 - Matsushita, K. A1 - Folsom, A. R. A1 - Shaw, J. E. A1 - Magliano, D. J. A1 - Zimmet, P. Z. A1 - Knuiman, M. W. A1 - Whincup, P. H. A1 - Wannamethee, S. G. A1 - Willeit, J. A1 - Santer, P. A1 - Egger, G. A1 - Casas, J. P. A1 - Amuzu, A. A1 - Ben-Shlomo, Y. A1 - Gallacher, J. A1 - Tikhonoff, V. A1 - Casiglia, E. A1 - Sutherland, S. E. A1 - Nietert, P. J. A1 - Cushman, M. A1 - Psaty, B. M. A1 - S?gaard, A. J. A1 - H?heim, L. L. A1 - Ariansen, I. A1 - Tybj?rg-Hansen, A. A1 - Jensen, G. B. A1 - Schnohr, P. A1 - Giampaoli, S. A1 - Vanuzzo, D. A1 - Panico, S. A1 - Palmieri, L. A1 - Balkau, B. A1 - Bonnet, F. A1 - Marre, M. A1 - de la C?mara, A. G. A1 - Rubio Herrera, M. A. A1 - Friedlander, Y. A1 - McCallum, J. A1 - McLachlan, S. A1 - Guralnik, J. A1 - Phillips, C. L. A1 - Khaw, K. T. A1 - Wareham, N. A1 - Sch?ttker, B. A1 - Saum, K. U. A1 - Holleczek, B. A1 - Nissinen, A. A1 - Tolonen, H. A1 - Giampaoli, S. A1 - Donfrancesco, C. A1 - Vartiainen, E. A1 - Jousilahti, P. A1 - Harald, K. A1 - D?Agostino, R. B. A1 - Massaro, J. M. A1 - Pencina, M. A1 - Vasan, R. A1 - Kayama, T. A1 - Kato, T. A1 - Oizumi, T. A1 - Jespersen, J. A1 - M?ller, L. A1 - Bladbjerg, E. M. A1 - Chetrit, A. A1 - Rosengren, A. A1 - Wilhelmsen, L. A1 - Bj?rkelund, C. A1 - Lissner, L. A1 - Nagel, D. A1 - Dennison, E. A1 - Kiyohara, Y. A1 - Ninomiya, T. A1 - Doi, Y. A1 - Rodriguez, B. A1 - Nijpels, G. A1 - Stehouwer, C. D. A. A1 - Sato, S. A1 - Kazumasa, Y. A1 - Iso, H. A1 - Goldbourt, U. A1 - Salomaa, V. A1 - Vartiainen, E. A1 - Kurl, S. A1 - Tuomainen, T. P. A1 - Salonen, J. T. A1 - Visser, M. A1 - Deeg, D. J. H. A1 - Meade, T. W. A1 - Nilsson, P. M. A1 - Hedblad, B. A1 - Melander, O. A1 - De Boer, I. H. A1 - DeFilippis, A. P. A1 - Verschuren, W. M. M. A1 - Sattar, N. A1 - Watt, G. A1 - Meisinger, C. A1 - Koenig, W. A1 - Rosengren, A. A1 - Kuller, L. H. A1 - Tverdal, A. A1 - Gillum, R. F. A1 - Cooper, J. A. A1 - Kirkland, S. A1 - Shimbo, D. A1 - Shaffer, J. A1 - Sato, S. A1 - Kazumasa, Y. A1 - Iso, H. A1 - Ducimetiere, P. A1 - Bakker, S. J. L. A1 - van der Harst, P. A1 - Hillege, H. L. A1 - Crespo, C. J. A1 - Amouyel, P. A1 - Dallongeville, J. A1 - Assmann, G. A1 - Schulte, H. A1 - Trompet, S. A1 - Smit, R. A. J. A1 - Stott, D. J. A1 - van der Schouw, Y. T. A1 - Despr?s, J. P. A1 - Cantin, B. A1 - Dagenais, G. R. A1 - Laughlin, G. A1 - Wingard, D. A1 - Trevisan, M. A1 - Aspelund, T. A1 - Eiriksdottir, G. A1 - Gudmundsson, E. F. A1 - Ikram, A. A1 - van Rooij, F. J. A. A1 - Franco, O. H. A1 - Rueda-Ochoa, O. L. A1 - Muka, T. A1 - Glisic, M. A1 - Tunstall-Pedoe, H. A1 - V?lzke, H. A1 - Howard, B. V. A1 - Zhang, Y. A1 - Jolly, S. A1 - Gallacher, J. A1 - Davey-Smith, G. A1 - Can, G. A1 - Y?ksel, H. A1 - Nakagawa, H. A1 - Morikawa, Y. A1 - Miura, K. A1 - Nj?lstad, I. A1 - Ingelsson, M. A1 - Giedraitis, V. A1 - Ridker, P. M. A1 - Gaziano, J. M. A1 - Kivimaki, M. A1 - Shipley, M. A1 - Brunner, E. J. A1 - Arndt, V. A1 - Brenner, H. A1 - Cook, N. A1 - Ridker, P. M. A1 - Ford, I. A1 - Sattar, N. A1 - Iba?ez, A. M. A1 - Geleijnse, J. M. AB - 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.\ 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. VL - 40 ER - TY - JOUR T1 - {Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls JF - Nature Y1 - 2019 A1 - Flannick, J. A1 - Mercader, J. M. A1 - Fuchsberger, C. A1 - Udler, M. S. A1 - Mahajan, A. A1 - Wessel, J. A1 - Teslovich, T. M. A1 - Caulkins, L. A1 - Koesterer, R. A1 - Barajas-Olmos, F. A1 - Blackwell, T. W. A1 - Boerwinkle, E. A1 - Brody, J. A. A1 - Centeno-Cruz, F. A1 - Chen, L. A1 - Chen, S. A1 - Contreras-Cubas, C. A1 - C?rdova, E. A1 - Correa, A. A1 - Cortes, M. A1 - DeFronzo, R. A. A1 - Dolan, L. A1 - Drews, K. L. A1 - Elliott, A. A1 - Floyd, J. S. A1 - Gabriel, S. A1 - Garay-Sevilla, M. E. A1 - Garc?a-Ortiz, H. A1 - Gross, M. A1 - Han, S. A1 - Heard-Costa, N. L. A1 - Jackson, A. U. A1 - J?rgensen, M. E. A1 - Kang, H. M. A1 - Kelsey, M. A1 - Kim, B. J. A1 - Koistinen, H. A. A1 - Kuusisto, J. A1 - Leader, J. B. A1 - Linneberg, A. A1 - Liu, C. T. A1 - Liu, J. A1 - Lyssenko, V. A1 - Manning, A. K. A1 - Marcketta, A. A1 - Malacara-Hernandez, J. M. A1 - Mart?nez-Hern?ndez, A. A1 - Matsuo, K. A1 - Mayer-Davis, E. A1 - Mendoza-Caamal, E. A1 - Mohlke, K. L. A1 - Morrison, A. C. A1 - Ndungu, A. A1 - Ng, M. C. Y. A1 - O'Dushlaine, C. A1 - Payne, A. J. A1 - Pihoker, C. A1 - Post, W. S. A1 - Preuss, M. A1 - Psaty, B. M. A1 - Vasan, R. S. A1 - Rayner, N. W. A1 - Reiner, A. P. A1 - Revilla-Monsalve, C. A1 - Robertson, N. R. A1 - Santoro, N. A1 - Schurmann, C. A1 - So, W. Y. A1 - Sober?n, X. A1 - Stringham, H. M. A1 - Strom, T. M. A1 - Tam, C. H. T. A1 - Thameem, F. A1 - Tomlinson, B. A1 - Torres, J. M. A1 - Tracy, R. P. A1 - van Dam, R. M. A1 - Vujkovic, M. A1 - Wang, S. A1 - Welch, R. P. A1 - Witte, D. R. A1 - Wong, T. Y. A1 - Atzmon, G. A1 - Barzilai, N. A1 - Blangero, J. A1 - Bonnycastle, L. L. A1 - Bowden, D. W. A1 - Chambers, J. C. A1 - Chan, E. A1 - Cheng, C. Y. A1 - Cho, Y. S. A1 - Collins, F. S. A1 - de Vries, P. S. A1 - Duggirala, R. A1 - Glaser, B. A1 - Gonzalez, C. A1 - Gonzalez, M. E. A1 - Groop, L. A1 - Kooner, J. S. A1 - Kwak, S. H. A1 - Laakso, M. A1 - Lehman, D. M. A1 - Nilsson, P. A1 - Spector, T. D. A1 - Tai, E. S. A1 - Tuomi, T. A1 - Tuomilehto, J. A1 - Wilson, J. G. A1 - Aguilar-Salinas, C. A. A1 - Bottinger, E. A1 - Burke, B. A1 - Carey, D. J. A1 - Chan, J. C. N. A1 - Dupuis, J. A1 - Frossard, P. A1 - Heckbert, S. R. A1 - Hwang, M. Y. A1 - Kim, Y. J. A1 - Kirchner, H. L. A1 - Lee, J. Y. A1 - Lee, J. A1 - Loos, R. J. F. A1 - Ma, R. C. W. A1 - Morris, A. D. A1 - O'Donnell, C. J. A1 - Palmer, C. N. A. A1 - Pankow, J. A1 - Park, K. S. A1 - Rasheed, A. A1 - Saleheen, D. A1 - Sim, X. A1 - Small, K. S. A1 - Teo, Y. Y. A1 - Haiman, C. A1 - Hanis, C. L. A1 - Henderson, B. E. A1 - Orozco, L. A1 - Tusi?-Luna, T. A1 - Dewey, F. E. A1 - Baras, A. A1 - Gieger, C. A1 - Meitinger, T. A1 - Strauch, K. A1 - Lange, L. A1 - Grarup, N. A1 - Hansen, T. A1 - Pedersen, O. A1 - Zeitler, P. A1 - Dabelea, D. A1 - Abecasis, G. A1 - Bell, G. I. A1 - Cox, N. J. A1 - Seielstad, M. A1 - Sladek, R. A1 - Meigs, J. B. A1 - Rich, S. S. A1 - Rotter, J. I. A1 - Altshuler, D. A1 - Burtt, N. P. A1 - Scott, L. J. A1 - Morris, A. P. A1 - Florez, J. C. A1 - McCarthy, M. I. A1 - Boehnke, M. AB - Protein-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. VL - 570 ER - TY - JOUR T1 - {Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology JF - Am J Hum Genet Y1 - 2019 A1 - Spracklen, C. N. A1 - Karaderi, T. A1 - Yaghootkar, H. A1 - Schurmann, C. A1 - Fine, R. S. A1 - Kutalik, Z. A1 - Preuss, M. H. A1 - Lu, Y. A1 - Wittemans, L. B. L. A1 - Adair, L. S. A1 - Allison, M. A1 - Amin, N. A1 - Auer, P. L. A1 - Bartz, T. M. A1 - her, M. A1 - Boehnke, M. A1 - Borja, J. B. A1 - Bork-Jensen, J. A1 - Broer, L. A1 - Chasman, D. I. A1 - Chen, Y. I. A1 - Chirstofidou, P. A1 - Demirkan, A. A1 - van Duijn, C. M. A1 - Feitosa, M. F. A1 - Garcia, M. E. A1 - Graff, M. A1 - Grallert, H. A1 - Grarup, N. A1 - Guo, X. A1 - Haesser, J. A1 - Hansen, T. A1 - Harris, T. B. A1 - Highland, H. M. A1 - Hong, J. A1 - Ikram, M. A. A1 - Ingelsson, E. A1 - Jackson, R. A1 - Jousilahti, P. A1 - nen, M. A1 - Kizer, J. R. A1 - Kovacs, P. A1 - Kriebel, J. A1 - Laakso, M. A1 - Lange, L. A. A1 - ki, T. A1 - Li, J. A1 - Li-Gao, R. A1 - Lind, L. A1 - Luan, J. A1 - inen, L. P. A1 - MacGregor, S. A1 - Mackey, D. A. A1 - Mahajan, A. A1 - Mangino, M. A1 - ö, S. A1 - McCarthy, M. I. A1 - McKnight, B. A1 - Medina-Gomez, C. A1 - Meigs, J. B. A1 - Molnos, S. A1 - Mook-Kanamori, D. A1 - Morris, A. P. A1 - de Mutsert, R. A1 - Nalls, M. A. A1 - Nedeljkovic, I. A1 - North, K. E. A1 - Pennell, C. E. A1 - Pradhan, A. D. A1 - Province, M. A. A1 - Raitakari, O. T. A1 - Raulerson, C. K. A1 - Reiner, A. P. A1 - Ridker, P. M. A1 - Ripatti, S. A1 - Roberston, N. A1 - Rotter, J. I. A1 - Salomaa, V. A1 - rate, A. A. A1 - Sitlani, C. M. A1 - Spector, T. D. A1 - Strauch, K. A1 - Stumvoll, M. A1 - Taylor, K. D. A1 - Thuesen, B. A1 - njes, A. A1 - Uitterlinden, A. G. A1 - Venturini, C. A1 - Walker, M. A1 - Wang, C. A. A1 - Wang, S. A1 - Wareham, N. J. A1 - Willems, S. M. A1 - Willems van Dijk, K. A1 - Wilson, J. G. A1 - Wu, Y. A1 - Yao, J. A1 - Young, K. L. A1 - Langenberg, C. A1 - Frayling, T. M. A1 - inen, T. O. A1 - Lindgren, C. M. A1 - Loos, R. J. F. A1 - Mohlke, K. L. AB - ) 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. VL - 105 ER - TY - JOUR T1 - {Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology JF - Am J Hum Genet Y1 - 2019 A1 - Spracklen, C. N. A1 - Karaderi, T. A1 - Yaghootkar, H. A1 - Schurmann, C. A1 - Fine, R. S. A1 - Kutalik, Z. A1 - Preuss, M. H. A1 - Lu, Y. A1 - Wittemans, L. B. L. A1 - Adair, L. S. A1 - Allison, M. A1 - Amin, N. A1 - Auer, P. L. A1 - Bartz, T. M. A1 - her, M. A1 - Boehnke, M. A1 - Borja, J. B. A1 - Bork-Jensen, J. A1 - Broer, L. A1 - Chasman, D. I. A1 - Chen, Y. I. A1 - Chirstofidou, P. A1 - Demirkan, A. A1 - van Duijn, C. M. A1 - Feitosa, M. F. A1 - Garcia, M. E. A1 - Graff, M. A1 - Grallert, H. A1 - Grarup, N. A1 - Guo, X. A1 - Haesser, J. A1 - Hansen, T. A1 - Harris, T. B. A1 - Highland, H. M. A1 - Hong, J. A1 - Ikram, M. A. A1 - Ingelsson, E. A1 - Jackson, R. A1 - Jousilahti, P. A1 - nen, M. A1 - Kizer, J. R. A1 - Kovacs, P. A1 - Kriebel, J. A1 - Laakso, M. A1 - Lange, L. A. A1 - ki, T. A1 - Li, J. A1 - Li-Gao, R. A1 - Lind, L. A1 - Luan, J. A1 - inen, L. P. A1 - MacGregor, S. A1 - Mackey, D. A. A1 - Mahajan, A. A1 - Mangino, M. A1 - ö, S. A1 - McCarthy, M. I. A1 - McKnight, B. A1 - Medina-Gomez, C. A1 - Meigs, J. B. A1 - Molnos, S. A1 - Mook-Kanamori, D. A1 - Morris, A. P. A1 - de Mutsert, R. A1 - Nalls, M. A. A1 - Nedeljkovic, I. A1 - North, K. E. A1 - Pennell, C. E. A1 - Pradhan, A. D. A1 - Province, M. A. A1 - Raitakari, O. T. A1 - Raulerson, C. K. A1 - Reiner, A. P. A1 - Ridker, P. M. A1 - Ripatti, S. A1 - Roberston, N. A1 - Rotter, J. I. A1 - Salomaa, V. A1 - rate, A. A. A1 - Sitlani, C. M. A1 - Spector, T. D. A1 - Strauch, K. A1 - Stumvoll, M. A1 - Taylor, K. D. A1 - Thuesen, B. A1 - njes, A. A1 - Uitterlinden, A. G. A1 - Venturini, C. A1 - Walker, M. A1 - Wang, C. A. A1 - Wang, S. A1 - Wareham, N. J. A1 - Willems, S. M. A1 - Willems van Dijk, K. A1 - Wilson, J. G. A1 - Wu, Y. A1 - Yao, J. A1 - Young, K. L. A1 - Langenberg, C. A1 - Frayling, T. M. A1 - inen, T. O. A1 - Lindgren, C. M. A1 - Loos, R. J. F. A1 - Mohlke, K. L. VL - 105 ER - TY - JOUR T1 - Genetic architecture of subcortical brain structures in 38,851 individuals. JF - Nat Genet Y1 - 2019 A1 - Satizabal, Claudia L A1 - Adams, Hieab H H A1 - Hibar, Derrek P A1 - White, Charles C A1 - Knol, Maria J A1 - Stein, Jason L A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Jahanshad, Neda A1 - Roshchupkin, Gennady V A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Luciano, Michelle A1 - Hofer, Edith A1 - Teumer, Alexander A1 - van der Lee, Sven J A1 - Yang, Jingyun A1 - Yanek, Lisa R A1 - Lee, Tom V A1 - Li, Shuo A1 - Hu, Yanhui A1 - Koh, Jia Yu A1 - Eicher, John D A1 - Desrivières, Sylvane A1 - Arias-Vasquez, Alejandro A1 - Chauhan, Ganesh A1 - Athanasiu, Lavinia A1 - Rentería, Miguel E A1 - Kim, Sungeun A1 - Hoehn, David A1 - Armstrong, Nicola J A1 - Chen, Qiang A1 - Holmes, Avram J A1 - den Braber, Anouk A1 - Kloszewska, Iwona A1 - Andersson, Micael A1 - Espeseth, Thomas A1 - Grimm, Oliver A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Milaneschi, Yuri A1 - Papmeyer, Martina A1 - Axelsson, Tomas A1 - Ehrlich, Stefan A1 - Roiz-Santiañez, Roberto A1 - Kraemer, Bernd A1 - Håberg, Asta K A1 - Jones, Hannah J A1 - Pike, G Bruce A1 - Stein, Dan J A1 - Stevens, Allison A1 - Bralten, Janita A1 - Vernooij, Meike W A1 - Harris, Tamara B A1 - Filippi, Irina A1 - Witte, A Veronica A1 - Guadalupe, Tulio A1 - Wittfeld, Katharina A1 - Mosley, Thomas H A1 - Becker, James T A1 - Doan, Nhat Trung A1 - Hagenaars, Saskia P A1 - Saba, Yasaman A1 - Cuellar-Partida, Gabriel A1 - Amin, Najaf A1 - Hilal, Saima A1 - Nho, Kwangsik A1 - Mirza-Schreiber, Nazanin A1 - Arfanakis, Konstantinos A1 - Becker, Diane M A1 - Ames, David A1 - Goldman, Aaron L A1 - Lee, Phil H A1 - Boomsma, Dorret I A1 - Lovestone, Simon A1 - Giddaluru, Sudheer A1 - Le Hellard, Stephanie A1 - Mattheisen, Manuel A1 - Bohlken, Marc M A1 - Kasperaviciute, Dalia A1 - Schmaal, Lianne A1 - Lawrie, Stephen M A1 - Agartz, Ingrid A1 - Walton, Esther A1 - Tordesillas-Gutierrez, Diana A1 - Davies, Gareth E A1 - Shin, Jean A1 - Ipser, Jonathan C A1 - Vinke, Louis N A1 - Hoogman, Martine A1 - Jia, Tianye A1 - Burkhardt, Ralph A1 - Klein, Marieke A1 - Crivello, Fabrice A1 - Janowitz, Deborah A1 - Carmichael, Owen A1 - Haukvik, Unn K A1 - Aribisala, Benjamin S A1 - Schmidt, Helena A1 - Strike, Lachlan T A1 - Cheng, Ching-Yu A1 - Risacher, Shannon L A1 - Pütz, Benno A1 - Fleischman, Debra A A1 - Assareh, Amelia A A1 - Mattay, Venkata S A1 - Buckner, Randy L A1 - Mecocci, Patrizia A1 - Dale, Anders M A1 - Cichon, Sven A1 - Boks, Marco P A1 - Matarin, Mar A1 - Penninx, Brenda W J H A1 - Calhoun, Vince D A1 - Chakravarty, M Mallar A1 - Marquand, Andre F A1 - Macare, Christine A1 - Kharabian Masouleh, Shahrzad A1 - Oosterlaan, Jaap A1 - Amouyel, Philippe A1 - Hegenscheid, Katrin A1 - Rotter, Jerome I A1 - Schork, Andrew J A1 - Liewald, David C M A1 - de Zubicaray, Greig I A1 - Wong, Tien Yin A1 - Shen, Li A1 - Sämann, Philipp G A1 - Brodaty, Henry A1 - Roffman, Joshua L A1 - de Geus, Eco J C A1 - Tsolaki, Magda A1 - Erk, Susanne A1 - van Eijk, Kristel R A1 - Cavalleri, Gianpiero L A1 - van der Wee, Nic J A A1 - McIntosh, Andrew M A1 - Gollub, Randy L A1 - Bulayeva, Kazima B A1 - Bernard, Manon A1 - Richards, Jennifer S A1 - Himali, Jayandra J A1 - Loeffler, Markus A1 - Rommelse, Nanda A1 - Hoffmann, Wolfgang A1 - Westlye, Lars T A1 - Valdés Hernández, Maria C A1 - Hansell, Narelle K A1 - van Erp, Theo G M A1 - Wolf, Christiane A1 - Kwok, John B J A1 - Vellas, Bruno A1 - Heinz, Andreas A1 - Olde Loohuis, Loes M A1 - Delanty, Norman A1 - Ho, Beng-Choon A1 - Ching, Christopher R K A1 - Shumskaya, Elena A1 - Singh, Baljeet A1 - Hofman, Albert A1 - van der Meer, Dennis A1 - Homuth, Georg A1 - Psaty, Bruce M A1 - Bastin, Mark E A1 - Montgomery, Grant W A1 - Foroud, Tatiana M A1 - Reppermund, Simone A1 - Hottenga, Jouke-Jan A1 - Simmons, Andrew A1 - Meyer-Lindenberg, Andreas A1 - Cahn, Wiepke A1 - Whelan, Christopher D A1 - van Donkelaar, Marjolein M J A1 - Yang, Qiong A1 - Hosten, Norbert A1 - Green, Robert C A1 - Thalamuthu, Anbupalam A1 - Mohnke, Sebastian A1 - Hulshoff Pol, Hilleke E A1 - Lin, Honghuang A1 - Jack, Clifford R A1 - Schofield, Peter R A1 - Mühleisen, Thomas W A1 - Maillard, Pauline A1 - Potkin, Steven G A1 - Wen, Wei A1 - Fletcher, Evan A1 - Toga, Arthur W A1 - Gruber, Oliver A1 - Huentelman, Matthew A1 - Davey Smith, George A1 - Launer, Lenore J A1 - Nyberg, Lars A1 - Jönsson, Erik G A1 - Crespo-Facorro, Benedicto A1 - Koen, Nastassja A1 - Greve, Douglas N A1 - Uitterlinden, André G A1 - Weinberger, Daniel R A1 - Steen, Vidar M A1 - Fedko, Iryna O A1 - Groenewold, Nynke A A1 - Niessen, Wiro J A1 - Toro, Roberto A1 - Tzourio, Christophe A1 - Longstreth, William T A1 - Ikram, M Kamran A1 - Smoller, Jordan W A1 - van Tol, Marie-Jose A1 - Sussmann, Jessika E A1 - Paus, Tomáš A1 - Lemaître, Hervé A1 - Schroeter, Matthias L A1 - Mazoyer, Bernard A1 - Andreassen, Ole A A1 - Holsboer, Florian A1 - Depondt, Chantal A1 - Veltman, Dick J A1 - Turner, Jessica A A1 - Pausova, Zdenka A1 - Schumann, Gunter A1 - van Rooij, Daan A1 - Djurovic, Srdjan A1 - Deary, Ian J A1 - McMahon, Katie L A1 - Müller-Myhsok, Bertram A1 - Brouwer, Rachel M A1 - Soininen, Hilkka A1 - Pandolfo, Massimo A1 - Wassink, Thomas H A1 - Cheung, Joshua W A1 - Wolfers, Thomas A1 - Martinot, Jean-Luc A1 - Zwiers, Marcel P A1 - Nauck, Matthias A1 - Melle, Ingrid A1 - Martin, Nicholas G A1 - Kanai, Ryota A1 - Westman, Eric A1 - Kahn, René S A1 - Sisodiya, Sanjay M A1 - White, Tonya A1 - Saremi, Arvin A1 - van Bokhoven, Hans A1 - Brunner, Han G A1 - Völzke, Henry A1 - Wright, Margaret J A1 - van 't Ent, Dennis A1 - Nöthen, Markus M A1 - Ophoff, Roel A A1 - Buitelaar, Jan K A1 - Fernández, Guillén A1 - Sachdev, Perminder S A1 - Rietschel, Marcella A1 - van Haren, Neeltje E M A1 - Fisher, Simon E A1 - Beiser, Alexa S A1 - Francks, Clyde A1 - Saykin, Andrew J A1 - Mather, Karen A A1 - Romanczuk-Seiferth, Nina A1 - Hartman, Catharina A A1 - DeStefano, Anita L A1 - Heslenfeld, Dirk J A1 - Weiner, Michael W A1 - Walter, Henrik A1 - Hoekstra, Pieter J A1 - Nyquist, Paul A A1 - Franke, Barbara A1 - Bennett, David A A1 - Grabe, Hans J A1 - Johnson, Andrew D A1 - Chen, Christopher A1 - van Duijn, Cornelia M A1 - Lopez, Oscar L A1 - Fornage, Myriam A1 - Wardlaw, Joanna M A1 - Schmidt, Reinhold A1 - DeCarli, Charles A1 - De Jager, Philip L A1 - Villringer, Arno A1 - Debette, Stephanie A1 - Gudnason, Vilmundur A1 - Medland, Sarah E A1 - Shulman, Joshua M A1 - Thompson, Paul M A1 - Seshadri, Sudha A1 - Ikram, M Arfan AB -

Subcortical 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.

VL - 51 IS - 11 ER - TY - JOUR T1 - Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. JF - Nat Genet Y1 - 2019 A1 - Kunkle, Brian W A1 - Grenier-Boley, Benjamin A1 - Sims, Rebecca A1 - Bis, Joshua C A1 - Damotte, Vincent A1 - Naj, Adam C A1 - Boland, Anne A1 - Vronskaya, Maria A1 - van der Lee, Sven J A1 - Amlie-Wolf, Alexandre A1 - Bellenguez, Céline A1 - Frizatti, Aura A1 - Chouraki, Vincent A1 - Martin, Eden R A1 - Sleegers, Kristel A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Hamilton-Nelson, Kara L A1 - Moreno-Grau, Sonia A1 - Olaso, Robert A1 - Raybould, Rachel A1 - Chen, Yuning A1 - Kuzma, Amanda B A1 - Hiltunen, Mikko A1 - Morgan, Taniesha A1 - Ahmad, Shahzad A1 - Vardarajan, Badri N A1 - Epelbaum, Jacques A1 - Hoffmann, Per A1 - Boada, Merce A1 - Beecham, Gary W A1 - Garnier, Jean-Guillaume A1 - Harold, Denise A1 - Fitzpatrick, Annette L A1 - Valladares, Otto A1 - Moutet, Marie-Laure A1 - Gerrish, Amy A1 - Smith, Albert V A1 - Qu, Liming A1 - Bacq, Delphine A1 - Denning, Nicola A1 - Jian, Xueqiu A1 - Zhao, Yi A1 - Del Zompo, Maria A1 - Fox, Nick C A1 - Choi, Seung-Hoan A1 - Mateo, Ignacio A1 - Hughes, Joseph T A1 - Adams, Hieab H A1 - Malamon, John A1 - Sanchez-Garcia, Florentino A1 - Patel, Yogen A1 - Brody, Jennifer A A1 - Dombroski, Beth A A1 - Naranjo, Maria Candida Deniz A1 - Daniilidou, Makrina A1 - Eiriksdottir, Gudny A1 - Mukherjee, Shubhabrata A1 - Wallon, David A1 - Uphill, James A1 - Aspelund, Thor A1 - Cantwell, Laura B A1 - Garzia, Fabienne A1 - Galimberti, Daniela A1 - Hofer, Edith A1 - Butkiewicz, Mariusz A1 - Fin, Bertrand A1 - Scarpini, Elio A1 - Sarnowski, Chloe A1 - Bush, Will S A1 - Meslage, Stéphane A1 - Kornhuber, Johannes A1 - White, Charles C A1 - Song, Yuenjoo A1 - Barber, Robert C A1 - Engelborghs, Sebastiaan A1 - Sordon, Sabrina A1 - Voijnovic, Dina A1 - Adams, Perrie M A1 - Vandenberghe, Rik A1 - Mayhaus, Manuel A1 - Cupples, L Adrienne A1 - Albert, Marilyn S A1 - De Deyn, Peter P A1 - Gu, Wei A1 - Himali, Jayanadra J A1 - Beekly, Duane A1 - Squassina, Alessio A1 - Hartmann, Annette M A1 - Orellana, Adelina A1 - Blacker, Deborah A1 - Rodriguez-Rodriguez, Eloy A1 - Lovestone, Simon A1 - Garcia, Melissa E A1 - Doody, Rachelle S A1 - Munoz-Fernadez, Carmen A1 - Sussams, Rebecca A1 - Lin, Honghuang A1 - Fairchild, Thomas J A1 - Benito, Yolanda A A1 - Holmes, Clive A1 - Karamujić-Čomić, Hata A1 - Frosch, Matthew P A1 - Thonberg, Håkan A1 - Maier, Wolfgang A1 - Roschupkin, Gena A1 - Ghetti, Bernardino A1 - Giedraitis, Vilmantas A1 - Kawalia, Amit A1 - Li, Shuo A1 - Huebinger, Ryan M A1 - Kilander, Lena A1 - Moebus, Susanne A1 - Hernandez, Isabel A1 - Kamboh, M Ilyas A1 - Brundin, RoseMarie A1 - Turton, James A1 - Yang, Qiong A1 - Katz, Mindy J A1 - Concari, Letizia A1 - Lord, Jenny A1 - Beiser, Alexa S A1 - Keene, C Dirk A1 - Helisalmi, Seppo A1 - Kloszewska, Iwona A1 - Kukull, Walter A A1 - Koivisto, Anne Maria A1 - Lynch, Aoibhinn A1 - Tarraga, Lluis A1 - Larson, Eric B A1 - Haapasalo, Annakaisa A1 - Lawlor, Brian A1 - Mosley, Thomas H A1 - Lipton, Richard B A1 - Solfrizzi, Vincenzo A1 - Gill, Michael A1 - Longstreth, W T A1 - Montine, Thomas J A1 - Frisardi, Vincenza A1 - Diez-Fairen, Monica A1 - Rivadeneira, Fernando A1 - Petersen, Ronald C A1 - Deramecourt, Vincent A1 - Alvarez, Ignacio A1 - Salani, Francesca A1 - Ciaramella, Antonio A1 - Boerwinkle, Eric A1 - Reiman, Eric M A1 - Fiévet, Nathalie A1 - Rotter, Jerome I A1 - Reisch, Joan S A1 - Hanon, Olivier A1 - Cupidi, Chiara A1 - Andre Uitterlinden, A G A1 - Royall, Donald R A1 - Dufouil, Carole A1 - Maletta, Raffaele Giovanni A1 - de Rojas, Itziar A1 - Sano, Mary A1 - Brice, Alexis A1 - Cecchetti, Roberta A1 - George-Hyslop, Peter St A1 - Ritchie, Karen A1 - Tsolaki, Magda A1 - Tsuang, Debby W A1 - Dubois, Bruno A1 - Craig, David A1 - Wu, Chuang-Kuo A1 - Soininen, Hilkka A1 - Avramidou, Despoina A1 - Albin, Roger L A1 - Fratiglioni, Laura A1 - Germanou, Antonia A1 - Apostolova, Liana G A1 - Keller, Lina A1 - Koutroumani, Maria A1 - Arnold, Steven E A1 - Panza, Francesco A1 - Gkatzima, Olymbia A1 - Asthana, Sanjay A1 - Hannequin, Didier A1 - Whitehead, Patrice A1 - Atwood, Craig S A1 - Caffarra, Paolo A1 - Hampel, Harald A1 - Quintela, Inés A1 - Carracedo, Angel A1 - Lannfelt, Lars A1 - Rubinsztein, David C A1 - Barnes, Lisa L A1 - Pasquier, Florence A1 - Frölich, Lutz A1 - Barral, Sandra A1 - McGuinness, Bernadette A1 - Beach, Thomas G A1 - Johnston, Janet A A1 - Becker, James T A1 - Passmore, Peter A1 - Bigio, Eileen H A1 - Schott, Jonathan M A1 - Bird, Thomas D A1 - Warren, Jason D A1 - Boeve, Bradley F A1 - Lupton, Michelle K A1 - Bowen, James D A1 - Proitsi, Petra A1 - Boxer, Adam A1 - Powell, John F A1 - Burke, James R A1 - Kauwe, John S K A1 - Burns, Jeffrey M A1 - Mancuso, Michelangelo A1 - Buxbaum, Joseph D A1 - Bonuccelli, Ubaldo A1 - Cairns, Nigel J A1 - McQuillin, Andrew A1 - Cao, Chuanhai A1 - Livingston, Gill A1 - Carlson, Chris S A1 - Bass, Nicholas J A1 - Carlsson, Cynthia M A1 - Hardy, John A1 - Carney, Regina M A1 - Bras, Jose A1 - Carrasquillo, Minerva M A1 - Guerreiro, Rita A1 - Allen, Mariet A1 - Chui, Helena C A1 - Fisher, Elizabeth A1 - Masullo, Carlo A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Bisceglio, Gina A1 - Dick, Malcolm A1 - Ma, Li A1 - Duara, Ranjan A1 - Graff-Radford, Neill R A1 - Evans, Denis A A1 - Hodges, Angela A1 - Faber, Kelley M A1 - Scherer, Martin A1 - Fallon, Kenneth B A1 - Riemenschneider, Matthias A1 - Fardo, David W A1 - Heun, Reinhard A1 - Farlow, Martin R A1 - Kölsch, Heike A1 - Ferris, Steven A1 - Leber, Markus A1 - Foroud, Tatiana M A1 - Heuser, Isabella A1 - Galasko, Douglas R A1 - Giegling, Ina A1 - Gearing, Marla A1 - Hüll, Michael A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Morris, John A1 - Green, Robert C A1 - Mayo, Kevin A1 - Growdon, John H A1 - Feulner, Thomas A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Drichel, Dmitriy A1 - Honig, Lawrence S A1 - Cushion, Thomas D A1 - Huentelman, Matthew J A1 - Hollingworth, Paul A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Marshall, Rachel A1 - Jarvik, Gail P A1 - Meggy, Alun A1 - Abner, Erin A1 - Menzies, Georgina E A1 - Jin, Lee-Way A1 - Leonenko, Ganna A1 - Real, Luis M A1 - Jun, Gyungah R A1 - Baldwin, Clinton T A1 - Grozeva, Detelina A1 - Karydas, Anna A1 - Russo, Giancarlo A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Jessen, Frank A1 - Kowall, Neil W A1 - Vellas, Bruno A1 - Kramer, Joel H A1 - Vardy, Emma A1 - LaFerla, Frank M A1 - Jöckel, Karl-Heinz A1 - Lah, James J A1 - Dichgans, Martin A1 - Leverenz, James B A1 - Mann, David A1 - Levey, Allan I A1 - Pickering-Brown, Stuart A1 - Lieberman, Andrew P A1 - Klopp, Norman A1 - Lunetta, Kathryn L A1 - Wichmann, H-Erich A1 - Lyketsos, Constantine G A1 - Morgan, Kevin A1 - Marson, Daniel C A1 - Brown, Kristelle A1 - Martiniuk, Frank A1 - Medway, Christopher A1 - Mash, Deborah C A1 - Nöthen, Markus M A1 - Masliah, Eliezer A1 - Hooper, Nigel M A1 - McCormick, Wayne C A1 - Daniele, Antonio A1 - McCurry, Susan M A1 - Bayer, Anthony A1 - McDavid, Andrew N A1 - Gallacher, John A1 - McKee, Ann C A1 - van den Bussche, Hendrik A1 - Mesulam, Marsel A1 - Brayne, Carol A1 - Miller, Bruce L A1 - Riedel-Heller, Steffi A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Al-Chalabi, Ammar A1 - Morris, John C A1 - Shaw, Christopher E A1 - Myers, Amanda J A1 - Wiltfang, Jens A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Alvarez, Victoria A1 - Parisi, Joseph E A1 - Singleton, Andrew B A1 - Paulson, Henry L A1 - Collinge, John A1 - Perry, William R A1 - Mead, Simon A1 - Peskind, Elaine A1 - Cribbs, David H A1 - Rossor, Martin A1 - Pierce, Aimee A1 - Ryan, Natalie S A1 - Poon, Wayne W A1 - Nacmias, Benedetta A1 - Potter, Huntington A1 - Sorbi, Sandro A1 - Quinn, Joseph F A1 - Sacchinelli, Eleonora A1 - Raj, Ashok A1 - Spalletta, Gianfranco A1 - Raskind, Murray A1 - Caltagirone, Carlo A1 - Bossù, Paola A1 - Orfei, Maria Donata A1 - Reisberg, Barry A1 - Clarke, Robert A1 - Reitz, Christiane A1 - Smith, A David A1 - Ringman, John M A1 - Warden, Donald A1 - Roberson, Erik D A1 - Wilcock, Gordon A1 - Rogaeva, Ekaterina A1 - Bruni, Amalia Cecilia A1 - Rosen, Howard J A1 - Gallo, Maura A1 - Rosenberg, Roger N A1 - Ben-Shlomo, Yoav A1 - Sager, Mark A A1 - Mecocci, Patrizia A1 - Saykin, Andrew J A1 - Pastor, Pau A1 - Cuccaro, Michael L A1 - Vance, Jeffery M A1 - Schneider, Julie A A1 - Schneider, Lori S A1 - Slifer, Susan A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tang, Mitchell A1 - Tanzi, Rudolph E A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Saba, Yasaman A1 - Pilotto, Alberto A1 - Bullido, María J A1 - Peters, Oliver A1 - Crane, Paul K A1 - Bennett, David A1 - Bosco, Paola A1 - Coto, Eliecer A1 - Boccardi, Virginia A1 - De Jager, Phil L A1 - Lleo, Alberto A1 - Warner, Nick A1 - Lopez, Oscar L A1 - Ingelsson, Martin A1 - Deloukas, Panagiotis A1 - Cruchaga, Carlos A1 - Graff, Caroline A1 - Gwilliam, Rhian A1 - Fornage, Myriam A1 - Goate, Alison M A1 - Sánchez-Juan, Pascual A1 - Kehoe, Patrick G A1 - Amin, Najaf A1 - Ertekin-Taner, Nilifur A1 - Berr, Claudine A1 - Debette, Stephanie A1 - Love, Seth A1 - Launer, Lenore J A1 - Younkin, Steven G A1 - Dartigues, Jean-François A1 - Corcoran, Chris A1 - Ikram, M Arfan A1 - Dickson, Dennis W A1 - Nicolas, Gaël A1 - Campion, Dominique A1 - Tschanz, JoAnn A1 - Schmidt, Helena A1 - Hakonarson, Hakon A1 - Clarimon, Jordi A1 - Munger, Ron A1 - Schmidt, Reinhold A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - C O'Donovan, Michael A1 - DeStefano, Anita L A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Deleuze, Jean-Francois A1 - Owen, Michael J A1 - Gudnason, Vilmundur A1 - Mayeux, Richard A1 - Escott-Price, Valentina A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Ruiz, Agustin A1 - van Duijn, Cornelia M A1 - Holmans, Peter A A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Amouyel, Phillippe A1 - Schellenberg, Gerard D A1 - Lambert, Jean-Charles A1 - Pericak-Vance, Margaret A AB -

Risk 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.

VL - 51 IS - 3 ER - TY - JOUR T1 - {Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria JF - Nat Commun Y1 - 2019 A1 - Teumer, A. A1 - Li, Y. A1 - Ghasemi, S. A1 - Prins, B. P. A1 - Wuttke, M. A1 - Hermle, T. A1 - Giri, A. A1 - Sieber, K. B. A1 - Qiu, C. A1 - Kirsten, H. A1 - Tin, A. A1 - Chu, A. Y. A1 - Bansal, N. A1 - Feitosa, M. F. A1 - Wang, L. A1 - Chai, J. F. A1 - Cocca, M. A1 - Fuchsberger, C. A1 - Gorski, M. A1 - Hoppmann, A. A1 - Horn, K. A1 - Li, M. A1 - Marten, J. A1 - Noce, D. A1 - Nutile, T. A1 - Sedaghat, S. A1 - Sveinbjornsson, G. A1 - Tayo, B. O. A1 - van der Most, P. J. A1 - Xu, Y. A1 - Yu, Z. A1 - Gerstner, L. A1 - ?rnl?v, J. A1 - Bakker, S. J. L. A1 - Baptista, D. A1 - Biggs, M. L. A1 - Boerwinkle, E. A1 - Brenner, H. A1 - Burkhardt, R. A1 - Carroll, R. J. A1 - Chee, M. L. A1 - Chee, M. L. A1 - Chen, M. A1 - Cheng, C. Y. A1 - Cook, J. P. A1 - Coresh, J. A1 - Corre, T. A1 - Danesh, J. A1 - de Borst, M. H. A1 - De Grandi, A. A1 - de Mutsert, R. A1 - de Vries, A. P. J. A1 - Degenhardt, F. A1 - Dittrich, K. A1 - Divers, J. A1 - Eckardt, K. U. A1 - Ehret, G. A1 - Endlich, K. A1 - Felix, J. F. A1 - Franco, O. H. A1 - Franke, A. A1 - Freedman, B. I. A1 - Freitag-Wolf, S. A1 - Gansevoort, R. T. A1 - Giedraitis, V. A1 - G?gele, M. A1 - Grundner-Culemann, F. A1 - Gudbjartsson, D. F. A1 - Gudnason, V. A1 - Hamet, P. A1 - Harris, T. B. A1 - Hicks, A. A. A1 - Holm, H. A1 - Foo, V. H. X. A1 - Hwang, S. J. A1 - Ikram, M. A. A1 - Ingelsson, E. A1 - Jaddoe, V. W. V. A1 - Jakobsdottir, J. A1 - Josyula, N. S. A1 - Jung, B. A1 - K?h?nen, M. A1 - Khor, C. C. A1 - Kiess, W. A1 - Koenig, W. A1 - K?rner, A. A1 - Kovacs, P. A1 - Kramer, H. A1 - Kr?mer, B. K. A1 - Kronenberg, F. A1 - Lange, L. A. A1 - Langefeld, C. D. A1 - Lee, J. J. A1 - Lehtim?ki, T. A1 - Lieb, W. A1 - Lim, S. C. A1 - Lind, L. A1 - Lindgren, C. M. A1 - Liu, J. A1 - Loeffler, M. A1 - Lyytik?inen, L. P. A1 - Mahajan, A. A1 - Maranville, J. C. A1 - Mascalzoni, D. A1 - McMullen, B. A1 - Meisinger, C. A1 - Meitinger, T. A1 - Miliku, K. A1 - Mook-Kanamori, D. O. A1 - M?ller-Nurasyid, M. A1 - Mychaleckyj, J. C. A1 - Nauck, M. A1 - Nikus, K. A1 - Ning, B. A1 - Noordam, R. A1 - Connell, J. O. A1 - Olafsson, I. A1 - Palmer, N. D. A1 - Peters, A. A1 - Podgornaia, A. I. A1 - Ponte, B. A1 - Poulain, T. A1 - Pramstaller, P. P. A1 - Rabelink, T. J. A1 - Raffield, L. M. A1 - Reilly, D. F. A1 - Rettig, R. A1 - Rheinberger, M. A1 - Rice, K. M. A1 - Rivadeneira, F. A1 - Runz, H. A1 - Ryan, K. A. A1 - Sabanayagam, C. A1 - Saum, K. U. A1 - Sch?ttker, B. A1 - Shaffer, C. M. A1 - Shi, Y. A1 - Smith, A. V. A1 - Strauch, K. A1 - Stumvoll, M. A1 - Sun, B. B. A1 - Szymczak, S. A1 - Tai, E. S. A1 - Tan, N. Y. Q. A1 - Taylor, K. D. A1 - Teren, A. A1 - Tham, Y. C. A1 - Thiery, J. A1 - Thio, C. H. L. A1 - Thomsen, H. A1 - Thorsteinsdottir, U. A1 - T?njes, A. A1 - Tremblay, J. A1 - Uitterlinden, A. G. A1 - van der Harst, P. A1 - Verweij, N. A1 - Vogelezang, S. A1 - V?lker, U. A1 - Waldenberger, M. A1 - Wang, C. A1 - Wilson, O. D. A1 - Wong, C. A1 - Wong, T. Y. A1 - Yang, Q. A1 - Yasuda, M. A1 - Akilesh, S. A1 - Bochud, M. A1 - B?ger, C. A. A1 - Devuyst, O. A1 - Edwards, T. L. A1 - Ho, K. A1 - Morris, A. P. A1 - Parsa, A. A1 - Pendergrass, S. A. A1 - Psaty, B. M. A1 - Rotter, J. I. A1 - Stefansson, K. A1 - Wilson, J. G. A1 - Susztak, K. A1 - Snieder, H. A1 - Heid, I. M. A1 - Scholz, M. A1 - Butterworth, A. S. A1 - Hung, A. M. A1 - Pattaro, C. A1 - K?ttgen, A. AB - Increased 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. VL - 10 ER - TY - JOUR T1 - {A genome-wide association study identifies genetic loci associated with specific lobar brain volumes JF - Commun Biol Y1 - 2019 A1 - van der Lee, S. J. A1 - Knol, M. J. A1 - Chauhan, G. A1 - Satizabal, C. L. A1 - Smith, A. V. A1 - Hofer, E. A1 - Bis, J. C. A1 - Hibar, D. P. A1 - Hilal, S. A1 - van den Akker, E. B. A1 - Arfanakis, K. A1 - Bernard, M. A1 - Yanek, L. R. A1 - Amin, N. A1 - Crivello, F. A1 - Cheung, J. W. A1 - Harris, T. B. A1 - Saba, Y. A1 - Lopez, O. L. A1 - Li, S. A1 - van der Grond, J. A1 - Yu, L. A1 - Paus, T. A1 - Roshchupkin, G. V. A1 - Amouyel, P. A1 - Jahanshad, N. A1 - Taylor, K. D. A1 - Yang, Q. A1 - Mathias, R. A. A1 - Boehringer, S. A1 - Mazoyer, B. A1 - Rice, K. A1 - Cheng, C. Y. A1 - Maillard, P. A1 - van Heemst, D. A1 - Wong, T. Y. A1 - Niessen, W. J. A1 - Beiser, A. S. A1 - Beekman, M. A1 - Zhao, W. A1 - Nyquist, P. A. A1 - Chen, C. A1 - Launer, L. J. A1 - Psaty, B. M. A1 - Ikram, M. K. A1 - Vernooij, M. W. A1 - Schmidt, H. A1 - Pausova, Z. A1 - Becker, D. M. A1 - De Jager, P. L. A1 - Thompson, P. M. A1 - van Duijn, C. M. A1 - Bennett, D. A. A1 - Slagboom, P. E. A1 - Schmidt, R. A1 - Longstreth, W. T. A1 - Ikram, M. A. A1 - Seshadri, S. A1 - Debette, S. A1 - Gudnason, V. A1 - Adams, H. H. H. A1 - DeCarli, C. AB - Brain 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. VL - 2 ER - TY - JOUR T1 - A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. JF - Blood Y1 - 2019 A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - Marten, Jonathan A1 - Song, Ci A1 - Pankratz, Nathan A1 - Bartz, Traci M A1 - de Haan, Hugoline G A1 - Delgado, Graciela E A1 - Eicher, John D A1 - Martinez-Perez, Angel A1 - Ward-Caviness, Cavin K A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - de Maat, Moniek P M A1 - Frånberg, Mattias A1 - Gill, Dipender A1 - Kleber, Marcus E A1 - Rivadeneira, Fernando A1 - Soria, José Manuel A1 - Tang, Weihong A1 - Tofler, Geoffrey H A1 - Uitterlinden, André G A1 - van Hylckama Vlieg, Astrid A1 - Seshadri, Sudha A1 - Boerwinkle, Eric A1 - Davies, Neil M A1 - Giese, Anne-Katrin A1 - Ikram, M Kamran A1 - Kittner, Steven J A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Reiner, Alex P A1 - Sargurupremraj, Muralidharan A1 - Taylor, Kent D A1 - Fornage, Myriam A1 - Hamsten, Anders A1 - März, Winfried A1 - Rosendaal, Frits R A1 - Souto, Juan Carlos A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Morrison, Alanna C A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L AB -

Factor 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.

VL - 133 IS - 9 ER - TY - JOUR T1 - {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group JF - Am J Hypertens Y1 - 2019 A1 - Irvin, M. R. A1 - Sitlani, C. M. A1 - Floyd, J. S. A1 - Psaty, B. M. A1 - Bis, J. C. A1 - Wiggins, K. L. A1 - Whitsel, E. A. A1 - Sturmer, T. A1 - Stewart, J. A1 - Raffield, L. A1 - Sun, F. A1 - Liu, C. T. A1 - Xu, H. A1 - Cupples, A. L. A1 - Tanner, R. M. A1 - Rossing, P. A1 - Smith, A. A1 - Zilh?o, N. R. A1 - Launer, L. J. A1 - Noordam, R. A1 - Rotter, J. I. A1 - Yao, J. A1 - Li, X. A1 - Guo, X. A1 - Limdi, N. A1 - Sundaresan, A. A1 - Lange, L. A1 - Correa, A. A1 - Stott, D. J. A1 - Ford, I. A1 - Jukema, J. W. A1 - Gudnason, V. A1 - Mook-Kanamori, D. O. A1 - Trompet, S. A1 - Palmas, W. A1 - Warren, H. R. A1 - Hellwege, J. N. A1 - Giri, A. A1 - O'Donnell, C. A1 - Hung, A. M. A1 - Edwards, T. L. A1 - Ahluwalia, T. S. A1 - Arnett, D. K. A1 - Avery, C. L. AB - {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 = 931 VL - 32 ER - TY - JOUR T1 - Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. JF - Am J Hypertens Y1 - 2019 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Floyd, James S A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Stewart, James A1 - Raffield, Laura A1 - Sun, Fangui A1 - Liu, Ching-Ti A1 - Xu, Hanfei A1 - Cupples, Adrienne L A1 - Tanner, Rikki M A1 - Rossing, Peter A1 - Smith, Albert A1 - Zilhão, Nuno R A1 - Launer, Lenore J A1 - Noordam, Raymond A1 - Rotter, Jerome I A1 - Yao, Jie A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Limdi, Nita A1 - Sundaresan, Aishwarya A1 - Lange, Leslie A1 - Correa, Adolfo A1 - Stott, David J A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Gudnason, Vilmundur A1 - Mook-Kanamori, Dennis O A1 - Trompet, Stella A1 - Palmas, Walter A1 - Warren, Helen R A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - O'donnell, Christopher A1 - Hung, Adriana M A1 - Edwards, Todd L A1 - Ahluwalia, Tarunveer S A1 - Arnett, Donna K A1 - Avery, Christy L KW - Aged KW - Antihypertensive Agents KW - Black or African American KW - Blood Pressure KW - Case-Control Studies KW - DNA (Cytosine-5-)-Methyltransferases KW - DNA Methyltransferase 3A KW - DNA-Binding Proteins KW - Drug Resistance KW - Dystrophin-Associated Proteins KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Myosin Heavy Chains KW - Myosin Type V KW - Neuropeptides KW - Pharmacogenetics KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Risk Factors KW - Transcription Factors KW - United States KW - White People AB -

BACKGROUND: 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.

VL - 32 IS - 12 ER - TY - JOUR T1 - Genome-wide association study of breakfast skipping links clock regulation with food timing. JF - Am J Clin Nutr Y1 - 2019 A1 - Dashti, Hassan S A1 - Merino, Jordi A1 - Lane, Jacqueline M A1 - Song, Yanwei A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - McKeown, Nicola M A1 - Tucker, Chandler A1 - Sun, Dianjianyi A1 - Bartz, Traci M A1 - Li-Gao, Ruifang A1 - Nisa, Hoirun A1 - Reutrakul, Sirimon A1 - Lemaitre, Rozenn N A1 - Alshehri, Tahani M A1 - de Mutsert, Renée A1 - Bazzano, Lydia A1 - Qi, Lu A1 - Knutson, Kristen L A1 - Psaty, Bruce M A1 - Mook-Kanamori, Dennis O A1 - Perica, Vesna Boraska A1 - Neuhouser, Marian L A1 - Scheer, Frank A J L A1 - Rutter, Martin K A1 - Garaulet, Marta A1 - Saxena, Richa AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink. JF - Clin Pharmacol Ther Y1 - 2019 A1 - Carr, Daniel F A1 - Francis, Ben A1 - Jorgensen, Andrea L A1 - Zhang, Eunice A1 - Chinoy, Hector A1 - Heckbert, Susan R A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Floyd, James S A1 - Psaty, Bruce M A1 - Molokhia, Mariam A1 - Lapeyre-Mestre, Maryse A1 - Conforti, Anita A1 - Alfirevic, Ana A1 - van Staa, Tjeerd A1 - Pirmohamed, Munir KW - Adverse Drug Reaction Reporting Systems KW - Case-Control Studies KW - Databases, Factual KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Liver-Specific Organic Anion Transporter 1 KW - Muscular Diseases KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results KW - Risk Factors KW - Severity of Illness Index KW - United Kingdom AB -

Statins 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.

VL - 106 IS - 6 ER - TY - JOUR T1 - {Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels JF - Circulation Y1 - 2019 A1 - Sabater-Lleal, M. A1 - Huffman, J. E. A1 - de Vries, P. S. A1 - Marten, J. A1 - Mastrangelo, M. A. A1 - Song, C. A1 - Pankratz, N. A1 - Ward-Caviness, C. K. A1 - Yanek, L. R. A1 - Trompet, S. A1 - Delgado, G. E. A1 - Guo, X. A1 - Bartz, T. M. A1 - Martinez-Perez, A. A1 - Germain, M. A1 - de Haan, H. G. A1 - Ozel, A. B. A1 - Polasek, O. A1 - Smith, A. V. A1 - Eicher, J. D. A1 - Reiner, A. P. A1 - Tang, W. A1 - Davies, N. M. A1 - Stott, D. J. A1 - Rotter, J. I. A1 - Tofler, G. H. A1 - Boerwinkle, E. A1 - de Maat, M. P. M. A1 - Kleber, M. E. A1 - Welsh, P. A1 - Brody, J. A. A1 - Chen, M. H. A1 - Vaidya, D. A1 - Soria, J. M. A1 - Suchon, P. A1 - van Hylckama Vlieg, A. A1 - Desch, K. C. A1 - Kolcic, I. A1 - Joshi, P. K. A1 - Launer, L. J. A1 - Harris, T. B. A1 - Campbell, H. A1 - Rudan, I. A1 - Becker, D. M. A1 - Li, J. Z. A1 - Rivadeneira, F. A1 - Uitterlinden, A. G. A1 - Hofman, A. A1 - Franco, O. H. A1 - Cushman, M. A1 - Psaty, B. M. A1 - Morange, P. E. A1 - McKnight, B. A1 - Chong, M. R. A1 - Fernandez-Cadenas, I. A1 - Rosand, J. A1 - Lindgren, A. A1 - Gudnason, V. A1 - Wilson, J. F. A1 - Hayward, C. A1 - Ginsburg, D. A1 - Fornage, M. A1 - Rosendaal, F. R. A1 - Souto, J. C. A1 - Becker, L. C. A1 - Jenny, N. S. A1 - M?rz, W. A1 - Jukema, J. W. A1 - Dehghan, A. A1 - Tr?gou?t, D. A. A1 - Morrison, A. C. A1 - Johnson, A. D. A1 - O'Donnell, C. J. A1 - Strachan, D. P. A1 - Lowenstein, C. J. A1 - Smith, N. L. AB - 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.\ 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. VL - 139 ER - TY - JOUR T1 - Genome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans. JF - Mol Genet Genomic Med Y1 - 2019 A1 - Do, Anh N A1 - Zhao, Wei A1 - Baldridge, Abigail S A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - Shah, Sanjiv J A1 - Aslibekyan, Stella A1 - Tiwari, Hemant K A1 - Limdi, Nita A1 - Zhi, Degui A1 - Sitlani, Colleen M A1 - Taylor, Kent D A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Brody, Jennifer A A1 - Rasmussen-Torvik, Laura J A1 - Lloyd-Jones, Donald A1 - Lange, Leslie A A1 - Wilson, James G A1 - Smith, Jennifer A A1 - Kardia, Sharon L R A1 - Mosley, Thomas H A1 - Vasan, Ramachandran S A1 - Arnett, Donna K A1 - Irvin, Marguerite R KW - African Americans KW - Angiotensin-Converting Enzyme Inhibitors KW - Antihypertensive Agents KW - Calcium Channel Blockers KW - Humans KW - Observational Studies as Topic KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Sodium Chloride Symporter Inhibitors KW - Ventricular Dysfunction, Left AB -

BACKGROUND: 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.

VL - 7 IS - 10 ER - TY - JOUR T1 - Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry. JF - Pharmacogenomics J Y1 - 2019 A1 - de Las Fuentes, L A1 - Sung, Y J A1 - Sitlani, C M A1 - Avery, C L A1 - Bartz, T M A1 - Keyser, C de A1 - Evans, D S A1 - Li, X A1 - Musani, S K A1 - Ruiter, R A1 - Smith, A V A1 - Sun, F A1 - Trompet, S A1 - Xu, H A1 - Arnett, D K A1 - Bis, J C A1 - Broeckel, U A1 - Busch, E L A1 - Chen, Y-D I A1 - Correa, A A1 - Cummings, S R A1 - Floyd, J S A1 - Ford, I A1 - Guo, X A1 - Harris, T B A1 - Ikram, M A A1 - Lange, L A1 - Launer, L J A1 - Reiner, A P A1 - Schwander, K A1 - Smith, N L A1 - Sotoodehnia, N A1 - Stewart, J D A1 - Stott, D J A1 - Stürmer, T A1 - Taylor, K D A1 - Uitterlinden, A A1 - Vasan, R S A1 - Wiggins, K L A1 - Cupples, L A A1 - Gudnason, V A1 - Heckbert, S R A1 - Jukema, J W A1 - Liu, Y A1 - Psaty, B M A1 - Rao, D C A1 - Rotter, J I A1 - Stricker, B A1 - Wilson, J G A1 - Whitsel, E A AB -

Hypertension (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.

ER - TY - JOUR T1 - Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. JF - Blood Y1 - 2019 A1 - Lindström, Sara A1 - Wang, Lu A1 - Smith, Erin N A1 - Gordon, William A1 - van Hylckama Vlieg, Astrid A1 - de Andrade, Mariza A1 - Brody, Jennifer A A1 - Pattee, Jack W A1 - Haessler, Jeffrey A1 - Brumpton, Ben M A1 - Chasman, Daniel I A1 - Suchon, Pierre A1 - Chen, Ming-Huei A1 - Turman, Constance A1 - Germain, Marine A1 - Wiggins, Kerri L A1 - MacDonald, James A1 - Braekkan, Sigrid K A1 - Armasu, Sebastian M A1 - Pankratz, Nathan A1 - Jackson, Rebecca D A1 - Nielsen, Jonas B A1 - Giulianini, Franco A1 - Puurunen, Marja K A1 - Ibrahim, Manal A1 - Heckbert, Susan R A1 - Damrauer, Scott M A1 - Natarajan, Pradeep A1 - Klarin, Derek A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - Bammler, Theo K A1 - Frazer, Kelly A A1 - McCauley, Bryan M A1 - Taylor, Kent A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Gabrielsen, Maiken E A1 - Deleuze, Jean-Francois A1 - O'Donnell, Chris J A1 - Kim, Jihye A1 - McKnight, Barbara A1 - Kraft, Peter A1 - Hansen, John-Bjarne A1 - Rosendaal, Frits R A1 - Heit, John A A1 - Psaty, Bruce M A1 - Tang, Weihong A1 - Kooperberg, Charles A1 - Hveem, Kristian A1 - Ridker, Paul M A1 - Morange, Pierre-Emmanuel A1 - Johnson, Andrew D A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Smith, Nicholas L AB -

Venous 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.

VL - 134 IS - 19 ER - TY - JOUR T1 - Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. JF - Elife Y1 - 2019 A1 - Timmers, Paul Rhj A1 - Mounier, Ninon A1 - Läll, Kristi A1 - Fischer, Krista A1 - Ning, Zheng A1 - Feng, Xiao A1 - Bretherick, Andrew D A1 - Clark, David W A1 - Agbessi, M A1 - Ahsan, H A1 - Alves, I A1 - Andiappan, A A1 - Awadalla, P A1 - Battle, A A1 - Bonder, M J A1 - Boomsma, D A1 - Christiansen, M A1 - Claringbould, A A1 - Deelen, P A1 - van Dongen, J A1 - Esko, T A1 - Favé, M A1 - Franke, L A1 - Frayling, T A1 - Gharib, S A A1 - Gibson, G A1 - Hemani, G A1 - Jansen, R A1 - Kalnapenkis, A A1 - Kasela, S A1 - Kettunen, J A1 - Kim, Y A1 - Kirsten, H A1 - Kovacs, P A1 - Krohn, K A1 - Kronberg-Guzman, J A1 - Kukushkina, V A1 - Kutalik, Z A1 - Kähönen, M A1 - Lee, B A1 - Lehtimäki, T A1 - Loeffler, M A1 - Marigorta, U A1 - Metspalu, A A1 - van Meurs, J A1 - Milani, L A1 - Müller-Nurasyid, M A1 - Nauck, M A1 - Nivard, M A1 - Penninx, B A1 - Perola, M A1 - Pervjakova, N A1 - Pierce, B A1 - Powell, J A1 - Prokisch, H A1 - Psaty, B M A1 - Raitakari, O A1 - Ring, S A1 - Ripatti, S A1 - Rotzschke, O A1 - Ruëger, S A1 - Saha, A A1 - Scholz, M A1 - Schramm, K A1 - Seppälä, I A1 - Stumvoll, M A1 - Sullivan, P A1 - Teumer, A A1 - Thiery, J A1 - Tong, L A1 - Tönjes, A A1 - Verlouw, J A1 - Visscher, P M A1 - Võsa, U A1 - Völker, U A1 - Yaghootkar, H A1 - Yang, J A1 - Zeng, B A1 - Zhang, F A1 - Agbessi, M A1 - Ahsan, H A1 - Alves, I A1 - Andiappan, A A1 - Awadalla, P A1 - Battle, A A1 - Bonder, M J A1 - Boomsma, D A1 - Christiansen, M A1 - Claringbould, A A1 - Deelen, P A1 - van Dongen, J A1 - Esko, T A1 - Favé, M A1 - Franke, L A1 - Frayling, T A1 - Gharib, S A A1 - Gibson, G A1 - Hemani, G A1 - Jansen, R A1 - Kalnapenkis, A A1 - Kasela, S A1 - Kettunen, J A1 - Kim, Y A1 - Kirsten, H A1 - Kovacs, P A1 - Krohn, K A1 - Kronberg-Guzman, J A1 - Kukushkina, V A1 - Kutalik, Z A1 - Kähönen, M A1 - Lee, B A1 - Lehtimäki, T A1 - Loeffler, M A1 - Marigorta, U A1 - Metspalu, A A1 - van Meurs, J A1 - Milani, L A1 - Müller-Nurasyid, M A1 - Nauck, M A1 - Nivard, M A1 - Penninx, B A1 - Perola, M A1 - Pervjakova, N A1 - Pierce, B A1 - Powell, J A1 - Prokisch, H A1 - Psaty, B M A1 - Raitakari, O A1 - Ring, S A1 - Ripatti, S A1 - Rotzschke, O A1 - Ruëger, S A1 - Saha, A A1 - Scholz, M A1 - Schramm, K A1 - Seppälä, I A1 - Stumvoll, M A1 - Sullivan, P A1 - Teumer, A A1 - Thiery, J A1 - Tong, L A1 - Tönjes, A A1 - Verlouw, J A1 - Visscher, P M A1 - Võsa, U A1 - Völker, U A1 - Yaghootkar, H A1 - Yang, J A1 - Zeng, B A1 - Zhang, F A1 - Shen, Xia A1 - Esko, Tõnu A1 - Kutalik, Zoltán A1 - Wilson, James F A1 - Joshi, Peter K AB -

We 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).

VL - 8 ER - TY - JOUR T1 - Heterogeneous Exposure Associations in Observational Cohort Studies: The Example of Blood Pressure in Older Adults. JF - Am J Epidemiol Y1 - 2019 A1 - Odden, Michelle C A1 - Rawlings, Andreea M A1 - Khodadadi, Abtin A1 - Fern, Xiaoli A1 - Shlipak, Michael G A1 - Bibbins-Domingo, Kirsten A1 - Covinsky, Kenneth A1 - Kanaya, Alka M A1 - Lee, Anne A1 - Haan, Mary N A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Peralta, Carmen A AB -

Heterogeneous 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.

ER - TY - JOUR T1 - {The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE) JF - PLoS One Y1 - 2019 A1 - Wolters, F. J. A1 - Yang, Q. A1 - Biggs, M. L. A1 - Jakobsdottir, J. A1 - Li, S. A1 - Evans, D. S. A1 - Bis, J. C. A1 - Harris, T. B. A1 - Vasan, R. S. A1 - Zilhao, N. R. A1 - Ghanbari, M. A1 - Ikram, M. A. A1 - Launer, L. A1 - Psaty, B. M. A1 - Tranah, G. J. A1 - Kulminski, A. M. A1 - Gudnason, V. A1 - Seshadri, S. AB - Apolipoprotein 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. VL - 14 ER - TY - JOUR T1 - Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. JF - Am J Hum Genet Y1 - 2019 A1 - Sarnowski, Chloe A1 - Leong, Aaron A1 - Raffield, Laura M A1 - Wu, Peitao A1 - de Vries, Paul S A1 - DiCorpo, Daniel A1 - Guo, Xiuqing A1 - Xu, Huichun A1 - Liu, Yongmei A1 - Zheng, Xiuwen A1 - Hu, Yao A1 - Brody, Jennifer A A1 - Goodarzi, Mark O A1 - Hidalgo, Bertha A A1 - Highland, Heather M A1 - Jain, Deepti A1 - Liu, Ching-Ti A1 - Naik, Rakhi P A1 - O'Connell, Jeffrey R A1 - Perry, James A A1 - Porneala, Bianca C A1 - Selvin, Elizabeth A1 - Wessel, Jennifer A1 - Psaty, Bruce M A1 - Curran, Joanne E A1 - Peralta, Juan M A1 - Blangero, John A1 - Kooperberg, Charles A1 - Mathias, Rasika A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Mitchell, Braxton D A1 - Cupples, L Adrienne A1 - Vasan, Ramachandran S A1 - Correa, Adolfo A1 - Morrison, Alanna C A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Manning, Alisa K A1 - Dupuis, Josée A1 - Meigs, James B AB -

Hemoglobin 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.

VL - 105 IS - 4 ER - TY - JOUR T1 - A large-scale exome array analysis of venous thromboembolism. JF - Genet Epidemiol Y1 - 2019 A1 - Lindström, Sara A1 - Brody, Jennifer A A1 - Turman, Constance A1 - Germain, Marine A1 - Bartz, Traci M A1 - Smith, Erin N A1 - Chen, Ming-Huei A1 - Puurunen, Marja A1 - Chasman, Daniel A1 - Hassler, Jeffrey A1 - Pankratz, Nathan A1 - Basu, Saonli A1 - Guan, Weihua A1 - Gyorgy, Beata A1 - Ibrahim, Manal A1 - Empana, Jean-Philippe A1 - Olaso, Robert A1 - Jackson, Rebecca A1 - Braekkan, Sigrid K A1 - McKnight, Barbara A1 - Deleuze, Jean-Francois A1 - O'Donnell, Cristopher J A1 - Jouven, Xavier A1 - Frazer, Kelly A A1 - Psaty, Bruce M A1 - Wiggins, Kerri L A1 - Taylor, Kent A1 - Reiner, Alexander P A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Ridker, Paul A1 - Hansen, John-Bjarne A1 - Tang, Weihong A1 - Johnson, Andrew D A1 - Morange, Pierre-Emmanuel A1 - Trégouët, David A A1 - Kraft, Peter A1 - Smith, Nicholas L A1 - Kabrhel, Christopher AB -

Although 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.

ER - TY - JOUR T1 - {Low thyroid function is not associated with an accelerated deterioration in renal function JF - Nephrol Dial Transplant Y1 - 2019 A1 - Meuwese, C. L. A1 - van Diepen, M. A1 - Cappola, A. R. A1 - Sarnak, M. J. A1 - Shlipak, M. G. A1 - Bauer, D. C. A1 - Fried, L. P. A1 - Iacoviello, M. A1 - Vaes, B. A1 - Degryse, J. A1 - Khaw, K. T. A1 - Luben, R. N. A1 - ?svold, B. O. A1 - Bj?ro, T. A1 - Vatten, L. J. A1 - de Craen, A. J. M. A1 - Trompet, S. A1 - Iervasi, G. A1 - Molinaro, S. A1 - Ceresini, G. A1 - Ferrucci, L. A1 - Dullaart, R. P. F. A1 - Bakker, S. J. L. A1 - Jukema, J. W. A1 - Kearney, P. M. A1 - Stott, D. J. A1 - Peeters, R. P. A1 - Franco, O. H. A1 - V?lzke, H. A1 - Walsh, J. P. A1 - Bremner, A. A1 - Sgarbi, J. A. A1 - Maciel, R. M. B. A1 - Imaizumi, M. A1 - Ohishi, W. A1 - Dekker, F. W. A1 - Rodondi, N. A1 - Gussekloo, J. A1 - den Elzen, W. P. J. AB - 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.\ 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. VL - 34 ER - TY - JOUR T1 - Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. JF - PLoS One Y1 - 2019 A1 - Ward-Caviness, Cavin K A1 - de Vries, Paul S A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Giulianini, Franco A1 - Guo, Xiuqing A1 - Kleber, Marcus E A1 - Kacprowski, Tim A1 - Groß, Stefan A1 - Petersman, Astrid A1 - Davey Smith, George A1 - Hartwig, Fernando P A1 - Bowden, Jack A1 - Hemani, Gibran A1 - Müller-Nuraysid, Martina A1 - Strauch, Konstantin A1 - Koenig, Wolfgang A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Pankratz, Nathan A1 - Boerwinkle, Eric A1 - Tang, Weihong A1 - Fu, Yi-Ping A1 - Johnson, Andrew D A1 - Song, Ci A1 - de Maat, Moniek P M A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Brody, Jennifer A A1 - McKnight, Barbara A1 - Chen, Yii-Der Ida A1 - Psaty, Bruce M A1 - Mathias, Rasika A A1 - Becker, Diane M A1 - Peyser, Patricia A A1 - Smith, Jennifer A A1 - Bielinski, Suzette J A1 - Ridker, Paul M A1 - Taylor, Kent D A1 - Yao, Jie A1 - Tracy, Russell A1 - Delgado, Graciela A1 - Trompet, Stella A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Rotter, Jerome I A1 - März, Winfried A1 - Dörr, Marcus A1 - Chasman, Daniel I A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Peters, Annette A1 - Morrison, Alanna C AB -

BACKGROUND: 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.

VL - 14 IS - 5 ER - TY - JOUR T1 - {A meta-analysis of genome-wide association studies identifies multiple longevity genes JF - Nat Commun Y1 - 2019 A1 - Deelen, J. A1 - Evans, D. S. A1 - Arking, D. E. A1 - Tesi, N. A1 - Nygaard, M. A1 - Liu, X. A1 - Wojczynski, M. K. A1 - Biggs, M. L. A1 - van der Spek, A. A1 - Atzmon, G. A1 - Ware, E. B. A1 - Sarnowski, C. A1 - Smith, A. V. A1 - Sepp?l?, I. A1 - Cordell, H. J. A1 - Dose, J. A1 - Amin, N. A1 - Arnold, A. M. A1 - Ayers, K. L. A1 - Barzilai, N. A1 - Becker, E. J. A1 - Beekman, M. A1 - Blanch?, H. A1 - Christensen, K. A1 - Christiansen, L. A1 - Collerton, J. C. A1 - Cubaynes, S. A1 - Cummings, S. R. A1 - Davies, K. A1 - Debrabant, B. A1 - Deleuze, J. F. A1 - Duncan, R. A1 - Faul, J. D. A1 - Franceschi, C. A1 - Galan, P. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Huisman, M. A1 - Hurme, M. A. A1 - Jagger, C. A1 - Jansen, I. A1 - Jylh?, M. A1 - K?h?nen, M. A1 - Karasik, D. A1 - Kardia, S. L. R. A1 - Kingston, A. A1 - Kirkwood, T. B. L. A1 - Launer, L. J. A1 - Lehtim?ki, T. A1 - Lieb, W. A1 - Lyytik?inen, L. P. A1 - Martin-Ruiz, C. A1 - Min, J. A1 - Nebel, A. A1 - Newman, A. B. A1 - Nie, C. A1 - Nohr, E. A. A1 - Orwoll, E. S. A1 - Perls, T. T. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Raitakari, O. T. A1 - Reinders, M. J. T. A1 - Robine, J. M. A1 - Rotter, J. I. A1 - Sebastiani, P. A1 - Smith, J. A1 - S?rensen, T. I. A. A1 - Taylor, K. D. A1 - Uitterlinden, A. G. A1 - van der Flier, W. A1 - van der Lee, S. J. A1 - van Duijn, C. M. A1 - van Heemst, D. A1 - Vaupel, J. W. A1 - Weir, D. A1 - Ye, K. A1 - Zeng, Y. A1 - Zheng, W. A1 - Holstege, H. A1 - Kiel, D. P. A1 - Lunetta, K. L. A1 - Slagboom, P. E. A1 - Murabito, J. M. AB - Human 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. VL - 10 ER - TY - JOUR T1 - {A meta-analysis of genome-wide association studies identifies multiple longevity genes JF - Nat Commun Y1 - 2019 A1 - Deelen, J. A1 - Evans, D. S. A1 - Arking, D. E. A1 - Tesi, N. A1 - Nygaard, M. A1 - Liu, X. A1 - Wojczynski, M. K. A1 - Biggs, M. L. A1 - van der Spek, A. A1 - Atzmon, G. A1 - Ware, E. B. A1 - Sarnowski, C. A1 - Smith, A. V. A1 - ä, I. A1 - Cordell, H. J. A1 - Dose, J. A1 - Amin, N. A1 - Arnold, A. M. A1 - Ayers, K. L. A1 - Barzilai, N. A1 - Becker, E. J. A1 - Beekman, M. A1 - é, H. A1 - Christensen, K. A1 - Christiansen, L. A1 - Collerton, J. C. A1 - Cubaynes, S. A1 - Cummings, S. R. A1 - Davies, K. A1 - Debrabant, B. A1 - Deleuze, J. F. A1 - Duncan, R. A1 - Faul, J. D. A1 - Franceschi, C. A1 - Galan, P. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Huisman, M. A1 - Hurme, M. A. A1 - Jagger, C. A1 - Jansen, I. A1 - ä, M. A1 - nen, M. A1 - Karasik, D. A1 - Kardia, S. L. R. A1 - Kingston, A. A1 - Kirkwood, T. B. L. A1 - Launer, L. J. A1 - ki, T. A1 - Lieb, W. A1 - inen, L. P. A1 - Martin-Ruiz, C. A1 - Min, J. A1 - Nebel, A. A1 - Newman, A. B. A1 - Nie, C. A1 - Nohr, E. A. A1 - Orwoll, E. S. A1 - Perls, T. T. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Raitakari, O. T. A1 - Reinders, M. J. T. A1 - Robine, J. M. A1 - Rotter, J. I. A1 - Sebastiani, P. A1 - Smith, J. A1 - rensen, T. I. A. A1 - Taylor, K. D. A1 - Uitterlinden, A. G. A1 - van der Flier, W. A1 - van der Lee, S. J. A1 - van Duijn, C. M. A1 - van Heemst, D. A1 - Vaupel, J. W. A1 - Weir, D. A1 - Ye, K. A1 - Zeng, Y. A1 - Zheng, W. A1 - Holstege, H. A1 - Kiel, D. P. A1 - Lunetta, K. L. A1 - Slagboom, P. E. A1 - Murabito, J. M. AB - 2) 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. VL - 10 ER - TY - JOUR T1 - {Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry JF - J Bone Miner Res Y1 - 2019 A1 - Hsu, Y. H. A1 - Estrada, K. A1 - Evangelou, E. A1 - Ackert-Bicknell, C. A1 - Akesson, K. A1 - Beck, T. A1 - Brown, S. J. A1 - Capellini, T. A1 - Carbone, L. A1 - Cauley, J. A1 - Cheung, C. L. A1 - Cummings, S. R. A1 - Czerwinski, S. A1 - Demissie, S. A1 - Econs, M. A1 - Evans, D. A1 - Farber, C. A1 - Gautvik, K. A1 - Harris, T. A1 - Kammerer, C. A1 - Kemp, J. A1 - Koller, D. L. A1 - Kung, A. A1 - Lawlor, D. A1 - Lee, M. A1 - Lorentzon, M. A1 - McGuigan, F. A1 - Medina-Gomez, C. A1 - Mitchell, B. A1 - Newman, A. A1 - Nielson, C. A1 - Ohlsson, C. A1 - Peacock, M. A1 - Reppe, S. A1 - Richards, J. B. A1 - Robbins, J. A1 - Sigurdsson, G. A1 - Spector, T. D. A1 - Stefansson, K. A1 - Streeten, E. A1 - Styrkarsdottir, U. A1 - Tobias, J. A1 - Trajanoska, K. A1 - Uitterlinden, A. A1 - Vandenput, L. A1 - Wilson, S. G. A1 - Yerges-Armstrong, L. A1 - Young, M. A1 - Zillikens, M. C. A1 - Rivadeneira, F. A1 - Kiel, D. P. A1 - Karasik, D. AB - Hip 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. VL - 34 ER - TY - JOUR T1 - Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. JF - Am J Epidemiol Y1 - 2019 A1 - de Vries, Paul S A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Kraja, Aldi T A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Deng, Xuan A1 - Dorajoo, Rajkumar A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Evangelou, Evangelos A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lee, Joseph H A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Riaz, Muhammad A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Connell, John M A1 - de Faire, Ulf A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Ding, Jingzhong A1 - Dominiczak, Anna F A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Grove, Megan L A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Steve B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lemaitre, Rozenn N A1 - Li, Yize A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Mukamal, Kenneth J A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tan, Nicholas A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Yujie A1 - Wang, Zhe A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Penninx, Brenda A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Zheng, Wei A1 - Elliott, Paul A1 - North, Kari E A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Kardia, Sharon L R A1 - Zhu, Xiaofeng A1 - Rotimi, Charles N A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Liu, Jingmin A1 - Rotter, Jerome I A1 - Gauderman, W James A1 - Province, Michael A A1 - Munroe, Patricia B A1 - Rice, Kenneth A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Morrison, Alanna C AB -

An 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.

ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. JF - Nat Genet Y1 - 2019 A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Brown, Michael R A1 - Winkler, Thomas W A1 - Kraja, Aldi T A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Chasman, Daniel I A1 - Lim, Elise A1 - Deng, Xuan A1 - Guo, Xiuqing A1 - Liu, Jingmin A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Baker, Jenna A1 - Chen, Guanjie A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Ding, Jingzhong A1 - Dorajoo, Rajkumar A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Zhao, Wei A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Hung, Yi-Jen A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lin, Keng-Hung A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Prins, Bram A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Tzung-Dau A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Xiang, Yong-Bing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Adeyemo, Adebowale A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Arzumanyan, Zorayr A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Cade, Brian E A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Christensen, Kaare A1 - Concas, Maria Pina A1 - Connell, John M A1 - de Las Fuentes, Lisa A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Doumatey, Ayo A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Floyd, James S A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gharib, Sina A A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Ikram, M Arfan A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Liang, Jingjing A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Louie, Tin A1 - Luzzi, Anna A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Tiemeier, Henning A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Heming A1 - Wang, Lan A1 - Wang, Lihua A1 - Wei, Wen Bin A1 - Williams, Christine A A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Young, Kristin A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhou, Jie A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Cooper, Richard S A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Juang, Jyh-Ming Jimmy A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Redline, Susan A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Jun-Sing A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zeggini, Eleftheria A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Province, Michael A A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Rotimi, Charles N A1 - Cupples, L Adrienne AB -

The 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.

VL - 51 IS - 4 ER - TY - JOUR T1 - {A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure JF - Hum. Mol. Genet. Y1 - 2019 A1 - Sung, Y. J. A1 - de Las Fuentes, L. A1 - Winkler, T. W. A1 - Chasman, D. I. A1 - Bentley, A. R. A1 - Kraja, A. T. A1 - Ntalla, I. A1 - Warren, H. R. A1 - Guo, X. A1 - Schwander, K. A1 - Manning, A. K. A1 - Brown, M. R. A1 - Aschard, H. A1 - Feitosa, M. F. A1 - Franceschini, N. A1 - Lu, Y. A1 - Cheng, C. Y. A1 - Sim, X. A1 - Vojinovic, D. A1 - Marten, J. A1 - Musani, S. K. A1 - Kilpel?inen, T. O. A1 - Richard, M. A. A1 - Aslibekyan, S. A1 - Bartz, T. M. A1 - Dorajoo, R. A1 - Li, C. A1 - Liu, Y. A1 - Rankinen, T. A1 - Smith, A. V. A1 - Tajuddin, S. M. A1 - Tayo, B. O. A1 - Zhao, W. A1 - Zhou, Y. A1 - Matoba, N. A1 - Sofer, T. A1 - Alver, M. A1 - Amini, M. A1 - Boissel, M. A1 - Chai, J. F. A1 - Chen, X. A1 - Divers, J. A1 - Gandin, I. A1 - Gao, C. A1 - Giulianini, F. A1 - Goel, A. A1 - Harris, S. E. A1 - Hartwig, F. P. A1 - He, M. A1 - Horimoto, A. R. V. R. A1 - Hsu, F. C. A1 - Jackson, A. U. A1 - Kammerer, C. M. A1 - Kasturiratne, A. A1 - Komulainen, P. A1 - K?hnel, B. A1 - Leander, K. A1 - Lee, W. J. A1 - Lin, K. H. A1 - Luan, J. A1 - Lyytik?inen, L. P. A1 - McKenzie, C. A. A1 - Nelson, C. P. A1 - Noordam, R. A1 - Scott, R. A. A1 - Sheu, W. H. H. A1 - Stan??kov?, A. A1 - Takeuchi, F. A1 - van der Most, P. J. A1 - Varga, T. V. A1 - Waken, R. J. A1 - Wang, H. A1 - Wang, Y. A1 - Ware, E. B. A1 - Weiss, S. A1 - Wen, W. A1 - Yanek, L. R. A1 - Zhang, W. A1 - Zhao, J. H. A1 - Afaq, S. A1 - Alfred, T. A1 - Amin, N. A1 - Arking, D. E. A1 - Aung, T. A1 - Barr, R. G. A1 - Bielak, L. F. A1 - Boerwinkle, E. A1 - Bottinger, E. P. A1 - Braund, P. S. A1 - Brody, J. A. A1 - Broeckel, U. A1 - Cade, B. A1 - Campbell, A. A1 - Canouil, M. A1 - Chakravarti, A. A1 - Cocca, M. A1 - Collins, F. S. A1 - Connell, J. M. A1 - de Mutsert, R. A1 - de Silva, H. J. A1 - D?rr, M. A1 - Duan, Q. A1 - Eaton, C. B. A1 - Ehret, G. A1 - Evangelou, E. A1 - Faul, J. D. A1 - Forouhi, N. G. A1 - Franco, O. H. A1 - Friedlander, Y. A1 - Gao, H. A1 - Gigante, B. A1 - Gu, C. C. A1 - Gupta, P. A1 - Hagenaars, S. P. A1 - Harris, T. B. A1 - He, J. A1 - Heikkinen, S. A1 - Heng, C. K. A1 - Hofman, A. A1 - Howard, B. V. A1 - Hunt, S. C. A1 - Irvin, M. R. A1 - Jia, Y. A1 - Katsuya, T. A1 - Kaufman, J. A1 - Kerrison, N. D. A1 - Khor, C. C. A1 - Koh, W. P. A1 - Koistinen, H. A. A1 - Kooperberg, C. B. A1 - Krieger, J. E. A1 - Kubo, M. A1 - Kutalik, Z. A1 - Kuusisto, J. A1 - Lakka, T. A. A1 - Langefeld, C. D. A1 - Langenberg, C. A1 - Launer, L. J. A1 - Lee, J. H. A1 - Lehne, B. A1 - Levy, D. A1 - Lewis, C. E. A1 - Li, Y. A1 - Lim, S. H. A1 - Liu, C. T. A1 - Liu, J. A1 - Liu, J. A1 - Liu, Y. A1 - Loh, M. A1 - Lohman, K. K. A1 - Louie, T. A1 - M?gi, R. A1 - Matsuda, K. A1 - Meitinger, T. A1 - Metspalu, A. A1 - Milani, L. A1 - Momozawa, Y. A1 - Mosley, T. H. A1 - Nalls, M. A. A1 - Nasri, U. A1 - O'Connell, J. R. A1 - Ogunniyi, A. A1 - Palmas, W. R. A1 - Palmer, N. D. A1 - Pankow, J. S. A1 - Pedersen, N. L. A1 - Peters, A. A1 - Peyser, P. A. A1 - Polasek, O. A1 - Porteous, D. A1 - Raitakari, O. T. A1 - Renstr?m, F. A1 - Rice, T. K. A1 - Ridker, P. M. A1 - Robino, A. A1 - Robinson, J. G. A1 - Rose, L. M. A1 - Rudan, I. A1 - Sabanayagam, C. A1 - Salako, B. L. A1 - Sandow, K. A1 - Schmidt, C. O. A1 - Schreiner, P. J. A1 - Scott, W. R. A1 - Sever, P. A1 - Sims, M. A1 - Sitlani, C. M. A1 - Smith, B. H. A1 - Smith, J. A. A1 - Snieder, H. A1 - Starr, J. M. A1 - Strauch, K. A1 - Tang, H. A1 - Taylor, K. D. A1 - Teo, Y. Y. A1 - Tham, Y. C. A1 - Uitterlinden, A. G. A1 - Waldenberger, M. A1 - Wang, L. A1 - Wang, Y. X. A1 - Wei, W. B. A1 - Wilson, G. A1 - Wojczynski, M. K. A1 - Xiang, Y. B. A1 - Yao, J. A1 - Yuan, J. M. A1 - Zonderman, A. B. A1 - Becker, D. M. A1 - Boehnke, M. A1 - Bowden, D. W. A1 - Chambers, J. C. A1 - Chen, Y. I. A1 - Weir, D. R. A1 - de Faire, U. A1 - Deary, I. J. A1 - Esko, T. A1 - Farrall, M. A1 - Forrester, T. A1 - Freedman, B. I. A1 - Froguel, P. A1 - Gasparini, P. A1 - Gieger, C. A1 - Horta, B. L. A1 - Hung, Y. J. A1 - Jonas, J. B. A1 - Kato, N. A1 - Kooner, J. S. A1 - Laakso, M. A1 - Lehtim?ki, T. A1 - Liang, K. W. A1 - Magnusson, P. K. E. A1 - Oldehinkel, A. J. A1 - Pereira, A. C. A1 - Perls, T. A1 - Rauramaa, R. A1 - Redline, S. A1 - Rettig, R. A1 - Samani, N. J. A1 - Scott, J. A1 - Shu, X. O. A1 - van der Harst, P. A1 - Wagenknecht, L. E. A1 - Wareham, N. J. A1 - Watkins, H. A1 - Wickremasinghe, A. R. A1 - Wu, T. A1 - Kamatani, Y. A1 - Laurie, C. C. A1 - Bouchard, C. A1 - Cooper, R. S. A1 - Evans, M. K. A1 - Gudnason, V. A1 - Hixson, J. A1 - Kardia, S. L. R. A1 - Kritchevsky, S. B. A1 - Psaty, B. M. A1 - van Dam, R. M. A1 - Arnett, D. K. A1 - Mook-Kanamori, D. O. A1 - Fornage, M. A1 - Fox, E. R. A1 - Hayward, C. A1 - van Duijn, C. M. A1 - Tai, E. S. A1 - Wong, T. Y. A1 - Loos, R. J. F. A1 - Reiner, A. P. A1 - Rotimi, C. N. A1 - Bierut, L. J. A1 - Zhu, X. A1 - Cupples, L. A. A1 - Province, M. A. A1 - Rotter, J. I. A1 - Franks, P. W. A1 - Rice, K. A1 - Elliott, P. A1 - Caulfield, M. J. A1 - Gauderman, W. J. A1 - Munroe, P. B. A1 - Rao, D. C. A1 - Morrison, A. C. AB - Elevated 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. ER - TY - JOUR T1 - Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. JF - Nat Commun Y1 - 2019 A1 - Noordam, Raymond A1 - Bos, Maxime M A1 - Wang, Heming A1 - Winkler, Thomas W A1 - Bentley, Amy R A1 - Kilpeläinen, Tuomas O A1 - de Vries, Paul S A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Cade, Brian E A1 - Manning, Alisa A1 - Aschard, Hugues A1 - Brown, Michael R A1 - Chen, Han A1 - Franceschini, Nora A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - de Las Fuentes, Lisa A1 - Feitosa, Mary A1 - Horimoto, Andrea R A1 - Ilkov, Marjan A1 - Kho, Minjung A1 - Kraja, Aldi A1 - Li, Changwei A1 - Lim, Elise A1 - Liu, Yongmei A1 - Mook-Kanamori, Dennis O A1 - Rankinen, Tuomo A1 - Tajuddin, Salman M A1 - van der Spek, Ashley A1 - Wang, Zhe A1 - Marten, Jonathan A1 - Laville, Vincent A1 - Alver, Maris A1 - Evangelou, Evangelos A1 - Graff, Maria E A1 - He, Meian A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Marques-Vidal, Pedro A1 - Nolte, Ilja M A1 - Palmer, Nicholette D A1 - Rauramaa, Rainer A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Adolfo, Correa A1 - Ballantyne, Christie A1 - Bielak, Larry A1 - Biermasz, Nienke R A1 - Boerwinkle, Eric A1 - Dimou, Niki A1 - Eiriksdottir, Gudny A1 - Gao, Chuan A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Haba-Rubio, José A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heinzer, Raphael A1 - Hixson, James E A1 - Homuth, Georg A1 - Ikram, M Arfan A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Lee, Jiwon A1 - Liu, Jingmin A1 - Lohman, Kurt K A1 - Luik, Annemarie I A1 - Mägi, Reedik A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Nalls, Mike A A1 - O'Connell, Jeff A1 - Peters, Annette A1 - Peyser, Patricia A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rensen, Patrick C N A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Roenneberg, Till A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Shikany, James A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Sofer, Tamar A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wallance, Robert B A1 - van Dijk, Ko Willems A1 - Yu, Caizheng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Penninx, Brenda W J H A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Xiang, Yong-Bing A1 - Zheng, Wei A1 - Arnett, Donna K A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Loos, Ruth J F A1 - Pereira, Alexandre C A1 - Province, Mike A1 - Psaty, Bruce M A1 - Rotimi, Charles A1 - Zhu, Xiaofeng A1 - Amin, Najaf A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin F A1 - Guo, Xiuqing A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Kooperberg, Charles A1 - Munroe, Patricia B A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - van Heemst, Diana A1 - Redline, Susan AB -

Both 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.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JF - Nat Commun Y1 - 2019 A1 - Kilpeläinen, Tuomas O A1 - Bentley, Amy R A1 - Noordam, Raymond A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Jakupović, Hermina A1 - Chasman, Daniel I A1 - Manning, Alisa A1 - Ntalla, Ioanna A1 - Aschard, Hugues A1 - Brown, Michael R A1 - de Las Fuentes, Lisa A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Feitosa, Mary F A1 - Kho, Minjung A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Wang, Heming A1 - Wang, Zhe A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Li, Changwei A1 - Lohman, Kurt K A1 - Marten, Jonathan A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Graff, Mariaelisa A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Zhao, Jing Hua A1 - Kraja, Aldi T A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Rueedi, Rico A1 - Stringham, Heather M A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Verweij, Niek A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Li, Xiaoyin A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Brumat, Marco A1 - Cade, Brian A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Concas, Maria Pina A1 - Connell, John A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Demirkan, Ayse A1 - Ding, Jingzhong A1 - Eaton, Charles B A1 - Faul, Jessica D A1 - Friedlander, Yechiel A1 - Gabriel, Kelley P A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven C A1 - Ikram, M Arfan A1 - Jonas, Jost B A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Leander, Karin A1 - Lemaitre, Rozenn N A1 - Lewis, Cora E A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Mägi, Reedik A1 - Manichaikul, Ani A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nang, Ei-Ei Khaing A1 - Nelson, Christopher P A1 - Nona, Sotoodehnia A1 - Norris, Jill M A1 - Nwuba, Chiamaka Vivian A1 - O'Connell, Jeff A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poveda, Alaitz A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Risch, Neil A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schreiner, Pamela J A1 - Scott, Robert A A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Starr, John M A1 - Sternfeld, Barbara A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - van der Ende, M Yldau A1 - van Heemst, Diana A1 - Voortman, Trudy A1 - Waldenberger, Melanie A1 - Wennberg, Patrik A1 - Wilson, Gregory A1 - Xiang, Yong-Bing A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - van Vliet-Ostaptchouk, Jana V A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wang, Ya X A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Evans, Michele K A1 - Franks, Paul W A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Liu, Yongmei A1 - North, Kari E A1 - Pereira, Alexandre C A1 - Ridker, Paul M A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - Fox, Ervin R A1 - Kardia, Sharon L R A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Redline, Susan A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Kooperberg, Charles B A1 - Gauderman, W James A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Fornage, Myriam A1 - Cupples, L Adrienne A1 - Rotimi, Charles N A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Loos, Ruth J F KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Brazil KW - Calcium-Binding Proteins KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Exercise KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Hispanic Americans KW - Humans KW - LIM-Homeodomain Proteins KW - Lipid Metabolism KW - Lipids KW - Male KW - Membrane Proteins KW - Microtubule-Associated Proteins KW - Middle Aged KW - Muscle Proteins KW - Nerve Tissue Proteins KW - Transcription Factors KW - Triglycerides KW - Young Adult AB -

Many 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.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. JF - Diabetes Y1 - 2019 A1 - Pollack, Samuela A1 - Igo, Robert P A1 - Jensen, Richard A A1 - Christiansen, Mark A1 - Li, Xiaohui A1 - Cheng, Ching-Yu A1 - Ng, Maggie C Y A1 - Smith, Albert V A1 - Rossin, Elizabeth J A1 - Segrè, Ayellet V A1 - Davoudi, Samaneh A1 - Tan, Gavin S A1 - Chen, Yii-Der Ida A1 - Kuo, Jane Z A1 - Dimitrov, Latchezar M A1 - Stanwyck, Lynn K A1 - Meng, Weihua A1 - Hosseini, S Mohsen A1 - Imamura, Minako A1 - Nousome, Darryl A1 - Kim, Jihye A1 - Hai, Yang A1 - Jia, Yucheng A1 - Ahn, Jeeyun A1 - Leong, Aaron A1 - Shah, Kaanan A1 - Park, Kyu Hyung A1 - Guo, Xiuqing A1 - Ipp, Eli A1 - Taylor, Kent D A1 - Adler, Sharon G A1 - Sedor, John R A1 - Freedman, Barry I A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Kubo, Michiaki A1 - Takahashi, Atsushi A1 - Hadjadj, Samy A1 - Marre, Michel A1 - Trégouët, David-Alexandre A1 - McKean-Cowdin, Roberta A1 - Varma, Rohit A1 - McCarthy, Mark I A1 - Groop, Leif A1 - Ahlqvist, Emma A1 - Lyssenko, Valeriya A1 - Agardh, Elisabet A1 - Morris, Andrew A1 - Doney, Alex S F A1 - Colhoun, Helen M A1 - Toppila, Iiro A1 - Sandholm, Niina A1 - Groop, Per-Henrik A1 - Maeda, Shiro A1 - Hanis, Craig L A1 - Penman, Alan A1 - Chen, Ching J A1 - Hancock, Heather A1 - Mitchell, Paul A1 - Craig, Jamie E A1 - Chew, Emily Y A1 - Paterson, Andrew D A1 - Grassi, Michael A A1 - Palmer, Colin A1 - Bowden, Donald W A1 - Yaspan, Brian L A1 - Siscovick, David A1 - Cotch, Mary Frances A1 - Wang, Jie Jin A1 - Burdon, Kathryn P A1 - Wong, Tien Y A1 - Klein, Barbara E K A1 - Klein, Ronald A1 - Rotter, Jerome I A1 - Iyengar, Sudha K A1 - Price, Alkes L A1 - Sobrin, Lucia AB -

To 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.

VL - 68 IS - 2 ER - TY - JOUR T1 - {New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders JF - Nat Hum Behav Y1 - 2019 A1 - Evangelou, E. A1 - Gao, H. A1 - Chu, C. A1 - Ntritsos, G. A1 - Blakeley, P. A1 - Butts, A. R. A1 - Pazoki, R. A1 - Suzuki, H. A1 - Koskeridis, F. A1 - Yiorkas, A. M. A1 - Karaman, I. A1 - Elliott, J. A1 - Luo, Q. A1 - Aeschbacher, S. A1 - Bartz, T. M. A1 - Baumeister, S. E. A1 - Braund, P. S. A1 - Brown, M. R. A1 - Brody, J. A. A1 - Clarke, T. K. A1 - Dimou, N. A1 - Faul, J. D. A1 - Homuth, G. A1 - Jackson, A. U. A1 - Kentistou, K. A. A1 - Joshi, P. K. A1 - Lemaitre, R. N. A1 - Lind, P. A. A1 - Lyytik?inen, L. P. A1 - Mangino, M. A1 - Milaneschi, Y. A1 - Nelson, C. P. A1 - Nolte, I. M. A1 - Per?l?, M. M. A1 - Polasek, O. A1 - Porteous, D. A1 - Ratliff, S. M. A1 - Smith, J. A. A1 - Stan??kov?, A. A1 - Teumer, A. A1 - Tuominen, S. A1 - Th?riault, S. A1 - Vangipurapu, J. A1 - Whitfield, J. B. A1 - Wood, A. A1 - Yao, J. A1 - Yu, B. A1 - Zhao, W. A1 - Arking, D. E. A1 - Auvinen, J. A1 - Liu, C. A1 - M?nnikk?, M. A1 - Risch, L. A1 - Rotter, J. I. A1 - Snieder, H. A1 - Veijola, J. A1 - Blakemore, A. I. A1 - Boehnke, M. A1 - Campbell, H. A1 - Conen, D. A1 - Eriksson, J. G. A1 - Grabe, H. J. A1 - Guo, X. A1 - van der Harst, P. A1 - Hartman, C. A. A1 - Hayward, C. A1 - Heath, A. C. A1 - Jarvelin, M. R. A1 - K?h?nen, M. A1 - Kardia, S. L. R. A1 - K?hne, M. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Lahti, J. A1 - Lehtim?ki, T. A1 - McIntosh, A. M. A1 - Mohlke, K. L. A1 - Morrison, A. C. A1 - Martin, N. G. A1 - Oldehinkel, A. J. A1 - Penninx, B. W. J. H. A1 - Psaty, B. M. A1 - Raitakari, O. T. A1 - Rudan, I. A1 - Samani, N. J. A1 - Scott, L. J. A1 - Spector, T. D. A1 - Verweij, N. A1 - Weir, D. R. A1 - Wilson, J. F. A1 - Levy, D. A1 - Tzoulaki, I. A1 - Bell, J. D. A1 - Matthews, P. M. A1 - Rothenfluh, A. A1 - Desrivi?res, S. A1 - Schumann, G. A1 - Elliott, P. AB - Excessive 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. VL - 3 ER - TY - JOUR T1 - NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure. JF - J Am Heart Assoc Y1 - 2019 A1 - Whitman, Isaac R A1 - Vittinghoff, Eric A1 - deFilippi, Christopher R A1 - Gottdiener, John S A1 - Alonso, Alvaro A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hoogeveen, Ron C A1 - Arking, Dan E A1 - Selvin, Elizabeth A1 - Chen, Lin Y A1 - Dewland, Thomas A A1 - Marcus, Gregory M AB -

Background 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.

VL - 8 IS - 7 ER - TY - JOUR T1 - {Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association JF - Am J Respir Crit Care Med Y1 - 2019 A1 - Xu, J. A1 - Gaddis, N. C. A1 - Bartz, T. M. A1 - Hou, R. A1 - Manichaikul, A. W. A1 - Pankratz, N. A1 - Smith, A. V. A1 - Sun, F. A1 - Terzikhan, N. A1 - Markunas, C. A. A1 - Patchen, B. K. A1 - Schu, M. A1 - Beydoun, M. A. A1 - Brusselle, G. G. A1 - Eiriksdottir, G. A1 - Zhou, X. A1 - Wood, A. C. A1 - Graff, M. A1 - Harris, T. B. A1 - Ikram, M. A. A1 - Jacobs, D. R. A1 - Launer, L. J. A1 - Lemaitre, R. N. A1 - O'Connor, G. T. A1 - Oelsner, E. C. A1 - Psaty, B. M. A1 - Vasan, R. S. A1 - Rohde, R. R. A1 - Rich, S. S. A1 - Rotter, J. I. A1 - Seshadri, S. A1 - Smith, L. J. A1 - Tiemeier, H. A1 - Tsai, M. Y. A1 - Uitterlinden, A. G. A1 - Voruganti, V. S. A1 - Xu, H. A1 - Zilh?o, N. R. A1 - Fornage, M. A1 - Zillikens, M. C. A1 - London, S. J. A1 - Barr, R. G. A1 - Dupuis, J. A1 - Gharib, S. A. A1 - Gudnason, V. A1 - Lahousse, L. A1 - North, K. E. A1 - Steffen, L. M. A1 - Cassano, P. A. A1 - Hancock, D. B. AB - Omega-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. VL - 199 ER - TY - JOUR T1 - Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. JF - PLoS One Y1 - 2019 A1 - Floyd, James S A1 - Bloch, Katarzyna M A1 - Brody, Jennifer A A1 - Maroteau, Cyrielle A1 - Siddiqui, Moneeza K A1 - Gregory, Richard A1 - Carr, Daniel F A1 - Molokhia, Mariam A1 - Liu, Xiaoming A1 - Bis, Joshua C A1 - Ahmed, Ammar A1 - Liu, Xuan A1 - Hallberg, Pär A1 - Yue, Qun-Ying A1 - Magnusson, Patrik K E A1 - Brisson, Diane A1 - Wiggins, Kerri L A1 - Morrison, Alanna C A1 - Khoury, Etienne A1 - McKeigue, Paul A1 - Stricker, Bruno H A1 - Lapeyre-Mestre, Maryse A1 - Heckbert, Susan R A1 - Gallagher, Arlene M A1 - Chinoy, Hector A1 - Gibbs, Richard A A1 - Bondon-Guitton, Emmanuelle A1 - Tracy, Russell A1 - Boerwinkle, Eric A1 - Gaudet, Daniel A1 - Conforti, Anita A1 - van Staa, Tjeerd A1 - Sitlani, Colleen M A1 - Rice, Kenneth M A1 - Maitland-van der Zee, Anke-Hilse A1 - Wadelius, Mia A1 - Morris, Andrew P A1 - Pirmohamed, Munir A1 - Palmer, Colin A N A1 - Psaty, Bruce M A1 - Alfirevic, Ana AB -

AIMS: 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.

VL - 14 IS - 6 ER - TY - JOUR T1 - Plasma Ceramides and Sphingomyelins in Relation to Heart Failure Risk. JF - Circ Heart Fail Y1 - 2019 A1 - Lemaitre, Rozenn N A1 - Jensen, Paul N A1 - Hoofnagle, Andrew A1 - McKnight, Barbara A1 - Fretts, Amanda M A1 - King, Irena B A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Mozaffarian, Dariush A1 - Sotoodehnia, Nona AB -

BACKGROUND: 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.

VL - 12 IS - 7 ER - TY - JOUR T1 - PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease. JF - J Neurosci Y1 - 2019 A1 - Fleck, Daniel A1 - Phu, Lilian A1 - Verschueren, Erik A1 - Hinkle, Trent A1 - Reichelt, Mike A1 - Bhangale, Tushar A1 - Haley, Benjamin A1 - Wang, Yuanyuan A1 - Graham, Robert A1 - Kirkpatrick, Donald S A1 - Sheng, Morgan A1 - Bingol, Baris AB -

In 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.

VL - 39 IS - 24 ER - TY - JOUR T1 - {Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis JF - BMJ Y1 - 2019 A1 - Merino, J. A1 - Guasch-Ferr?, M. A1 - Ellervik, C. A1 - Dashti, H. S. A1 - Sharp, S. J. A1 - Wu, P. A1 - Overvad, K. A1 - Sarnowski, C. A1 - Kuokkanen, M. A1 - Lemaitre, R. N. A1 - Justice, A. E. A1 - Ericson, U. A1 - Braun, K. V. E. A1 - Mahendran, Y. A1 - Frazier-Wood, A. C. A1 - Sun, D. A1 - Chu, A. Y. A1 - Tanaka, T. A1 - Luan, J. A1 - Hong, J. A1 - Tj?nneland, A. A1 - Ding, M. A1 - Lundqvist, A. A1 - Mukamal, K. A1 - Rohde, R. A1 - Schulz, C. A. A1 - Franco, O. H. A1 - Grarup, N. A1 - Chen, Y. I. A1 - Bazzano, L. A1 - Franks, P. W. A1 - Buring, J. E. A1 - Langenberg, C. A1 - Liu, C. T. A1 - Hansen, T. A1 - Jensen, M. K. A1 - S??ksj?rvi, K. A1 - Psaty, B. M. A1 - Young, K. L. A1 - Hindy, G. A1 - Sandholt, C. H. A1 - Ridker, P. M. A1 - Ordovas, J. M. A1 - Meigs, J. B. A1 - Pedersen, O. A1 - Kraft, P. A1 - Perola, M. A1 - North, K. E. A1 - Orho-Melander, M. A1 - Voortman, T. A1 - Toft, U. A1 - Rotter, J. I. A1 - Qi, L. A1 - Forouhi, N. G. A1 - Mozaffarian, D. A1 - S?rensen, T. I. A. A1 - Stampfer, M. J. A1 - M?nnist?, S. A1 - Selvin, E. A1 - Imamura, F. A1 - Salomaa, V. A1 - Hu, F. B. A1 - Wareham, N. J. A1 - Dupuis, J. A1 - Smith, C. E. A1 - Kilpel?inen, T. O. A1 - Chasman, D. I. A1 - Florez, J. C. AB - {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 1.75 VL - 366 ER - TY - JOUR T1 - A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. JF - Alzheimers Dement Y1 - 2019 A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Beecham, Gary A1 - Vardarajan, Badri N A1 - Ma, Yiyi A1 - Lancour, Daniel A1 - Farrell, John J A1 - Chung, Jaeyoon A1 - Mayeux, Richard A1 - Haines, Jonathan L A1 - Schellenberg, Gerard D A1 - Pericak-Vance, Margaret A A1 - Lunetta, Kathryn L A1 - Farrer, Lindsay A AB -

INTRODUCTION: 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.

ER - TY - JOUR T1 - {Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium JF - Am J Kidney Dis Y1 - 2019 A1 - Inker, L. A. A1 - Grams, M. E. A1 - Levey, A. S. A1 - Coresh, J. A1 - Cirillo, M. A1 - Collins, J. F. A1 - Gansevoort, R. T. A1 - Gutierrez, O. M. A1 - Hamano, T. A1 - Heine, G. H. A1 - Ishikawa, S. A1 - Jee, S. H. A1 - Kronenberg, F. A1 - Landray, M. J. A1 - Miura, K. A1 - Nadkarni, G. N. A1 - Peralta, C. A. A1 - Rothenbacher, D. A1 - Schaeffner, E. A1 - Sedaghat, S. A1 - Shlipak, M. G. A1 - Zhang, L. A1 - van Zuilen, A. D. A1 - Hallan, S. I. A1 - Kovesdy, C. P. A1 - Woodward, M. A1 - Levin, A. A1 - Astor, B. A1 - Appel, L. A1 - Greene, T. A1 - Chen, T. A1 - Chalmers, J. A1 - Woodward, M. A1 - Arima, H. A1 - Perkovic, V. A1 - Yatsuya, H. A1 - Tamakoshi, K. A1 - Li, Y. A1 - Hirakawa, Y. A1 - Coresh, J. A1 - Matsushita, K. A1 - Grams, M. A1 - Sang, Y. A1 - Polkinghorne, K. A1 - Chadban, S. A1 - Atkins, R. A1 - Levin, A. A1 - Djurdjev, O. A1 - Zhang, L. A1 - Liu, L. A1 - Zhao, M. A1 - Wang, F. A1 - Wang, J. A1 - Schaeffner, E. A1 - Ebert, N. A1 - Martus, P. A1 - Levin, A. A1 - Djurdjev, O. A1 - Tang, M. A1 - Heine, G. A1 - Emrich, I. A1 - Seiler, S. A1 - Zawada, A. A1 - Nally, J. A1 - Navaneethan, S. A1 - Schold, J. A1 - Zhang, L. A1 - Zhao, M. A1 - Wang, F. A1 - Wang, J. A1 - Shlipak, M. A1 - Sarnak, M. A1 - Katz, R. A1 - Hiramoto, J. A1 - Iso, H. A1 - Yamagishi, K. A1 - Umesawa, M. A1 - Muraki, I. A1 - Fukagawa, M. A1 - Maruyama, S. A1 - Hamano, T. A1 - Hasegawa, T. A1 - Fujii, N. A1 - Wheeler, D. A1 - Emberson, J. A1 - Townend, J. A1 - Landray, M. A1 - Brenner, H. A1 - Sch?ttker, B. A1 - Saum, K. U. A1 - Rothenbacher, D. A1 - Fox, C. A1 - Hwang, S. J. A1 - K?ttgen, A. A1 - Kronenberg, F. A1 - Schneider, M. P. A1 - Eckardt, K. U. A1 - Green, J. A1 - Kirchner, H. L. A1 - Chang, A. R. A1 - Ho, K. A1 - Ito, S. A1 - Miyazaki, M. A1 - Nakayama, M. A1 - Yamada, G. A1 - Cirillo, M. A1 - Irie, F. A1 - Sairenchi, T. A1 - Ishikawa, S. A1 - Yano, Y. A1 - Kotani, K. A1 - Nakamura, T. A1 - Jee, S. H. A1 - Kimm, H. A1 - Mok, Y. A1 - Chodick, G. A1 - Shalev, V. A1 - Wetzels, J. F. M. A1 - Blankestijn, P. J. A1 - van Zuilen, A. D. A1 - van den Brand, J. A1 - Sarnak, M. A1 - Inker, L. A1 - Peralta, C. A1 - Hiramoto, J. A1 - Katz, R. A1 - Sarnak, M. A1 - Kronenberg, F. A1 - Kollerits, B. A1 - Ritz, E. A1 - Nitsch, D. A1 - Roderick, P. A1 - Fletcher, A. A1 - Bottinger, E. A1 - Nadkarni, G. N. A1 - Ellis, S. B. A1 - Nadukuru, R. A1 - Sang, Y. A1 - Ueshima, H. A1 - Okayama, A. A1 - Miura, K. A1 - Tanaka, S. A1 - Ueshima, H. A1 - Okamura, T. A1 - Miura, K. A1 - Tanaka, S. A1 - Miura, K. A1 - Okayama, A. A1 - Kadota, A. A1 - Tanaka, S. A1 - Kenealy, T. A1 - Elley, C. R. A1 - Collins, J. F. A1 - Drury, P. L. A1 - Ohkubo, T. A1 - Asayama, K. A1 - Metoki, H. A1 - Kikuya, M. A1 - Nakayama, M. A1 - Nelson, R. G. A1 - Knowler, W. C. A1 - Gansevoort, R. T. A1 - Bakker, S. J. A1 - Hak, E. A1 - Heerspink, H. J. L. A1 - Brunskill, N. A1 - Major, R. A1 - Shepherd, D. A1 - Medcalf, J. A1 - Jassal, S. K. A1 - Bergstrom, J. A1 - Ix, J. H. A1 - Barrett-Connor, E. A1 - Kovesdy, C. A1 - Kalantar-Zadeh, K. A1 - Sumida, K. A1 - Gutierrez, O. M. A1 - Muntner, P. A1 - Warnock, D. A1 - McClellan, W. A1 - Heerspink, H. J. L. A1 - de Zeeuw, D. A1 - Brenner, B. A1 - Sedaghat, S. A1 - Ikram, M. A. A1 - Hoorn, E. J. A1 - Dehghan, A. A1 - Carrero, J. J. A1 - Gasparini, A. A1 - Wettermark, B. A1 - Elinder, C. G. A1 - Wong, T. Y. A1 - Sabanayagam, C. A1 - Cheng, C. Y. A1 - Visseren, F. L. J. A1 - Evans, M. A1 - Segelmark, M. A1 - Stendahl, M. A1 - Sch?n, S. A1 - Tangri, N. A1 - Sud, M. A1 - Naimark, D. A1 - Wen, C. P. A1 - Tsao, C. K. A1 - Tsai, M. K. A1 - Chen, C. H. A1 - Konta, T. A1 - Hirayama, A. A1 - Ichikawa, K. A1 - Lannfelt, L. A1 - Larsson, A. A1 - ?rnl?v, J. A1 - Bilo, H. J. G. A1 - Landman, G. W. D. A1 - van Hateren, K. J. J. A1 - Kleefstra, N. A1 - Coresh Chair, J. A1 - Gansevoort, R. T. A1 - Grams, M. E. A1 - Hallan, S. A1 - Kovesdy, C. P. A1 - Levey, A. S. A1 - Matsushita, K. A1 - Shalev, V. A1 - Woodward, M. A1 - Ballew, S. H. A1 - Chen, J. A1 - Coresh, J. A1 - Grams, M. E. A1 - Kwak, L. A1 - Matsushita, K. A1 - Sang, Y. A1 - Surapaneni, A. A1 - Woodward, M. AB - 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.\ 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. VL - 73 ER - TY - JOUR T1 - The role of functional status on the relationship between blood pressure and cognitive decline: the Cardiovascular Health Study. JF - J Hypertens Y1 - 2019 A1 - Miller, Lindsay M A1 - Peralta, Carmen A A1 - Fitzpatrick, Annette L A1 - Wu, Chenkai A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Odden, Michelle C AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. JF - Am J Hum Genet Y1 - 2019 A1 - Liang, Jingjing A1 - Cade, Brian E A1 - He, Karen Y A1 - Wang, Heming A1 - Lee, Jiwon A1 - Sofer, Tamar A1 - Williams, Stephanie A1 - Li, Ruitong A1 - Chen, Han A1 - Gottlieb, Daniel J A1 - Evans, Daniel S A1 - Guo, Xiuqing A1 - Gharib, Sina A A1 - Hale, Lauren A1 - Hillman, David R A1 - Lutsey, Pamela L A1 - Mukherjee, Sutapa A1 - Ochs-Balcom, Heather M A1 - Palmer, Lyle J A1 - Rhodes, Jessica A1 - Purcell, Shaun A1 - Patel, Sanjay R A1 - Saxena, Richa A1 - Stone, Katie L A1 - Tang, Weihong A1 - Tranah, Gregory J A1 - Boerwinkle, Eric A1 - Lin, Xihong A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Cho, Michael H A1 - Manichaikul, Ani A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Redline, Susan A1 - Zhu, Xiaofeng AB -

Average 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.

VL - 105 IS - 5 ER - TY - JOUR T1 - Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2019 A1 - Lai, Heidi T M A1 - de Oliveira Otto, Marcia C A1 - Lee, Yujin A1 - Wu, Jason H Y A1 - Song, Xiaoling A1 - King, Irena B A1 - Psaty, Bruce M A1 - Lemaitre, Rozenn N A1 - McKnight, Barbara A1 - Siscovick, David S A1 - Mozaffarian, Dariush AB -

Background 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.

VL - 8 IS - 22 ER - TY - JOUR T1 - Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study. JF - Pharmacogenomics J Y1 - 2019 A1 - Smit, Roelof A J A1 - Trompet, Stella A1 - Leong, Aaron A1 - Goodarzi, Mark O A1 - Postmus, Iris A1 - Warren, Helen A1 - Theusch, Elizabeth A1 - Barnes, Michael R A1 - Arsenault, Benoit J A1 - Li, Xiaohui A1 - Feng, QiPing A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Hitman, Graham A A1 - Krauss, Ronald M A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Cessie, Saskia le A1 - Stein, C Michael A1 - Jukema, J Wouter AB -

It 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.

ER - TY - JOUR T1 - Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. JF - Genome Biol Y1 - 2019 A1 - Ebbert, Mark T W A1 - Jensen, Tanner D A1 - Jansen-West, Karen A1 - Sens, Jonathon P A1 - Reddy, Joseph S A1 - Ridge, Perry G A1 - Kauwe, John S K A1 - Belzil, Veronique A1 - Pregent, Luc A1 - Carrasquillo, Minerva M A1 - Keene, Dirk A1 - Larson, Eric A1 - Crane, Paul A1 - Asmann, Yan W A1 - Ertekin-Taner, Nilufer A1 - Younkin, Steven G A1 - Ross, Owen A A1 - Rademakers, Rosa A1 - Petrucelli, Leonard A1 - Fryer, John D KW - Genetic Predisposition to Disease KW - Genome, Human KW - Humans KW - Mutation AB -

BACKGROUND: 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.

VL - 20 IS - 1 ER - TY - JOUR T1 - Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. JF - Nat Genet Y1 - 2019 A1 - Tin, Adrienne A1 - Marten, Jonathan A1 - Halperin Kuhns, Victoria L A1 - Li, Yong A1 - Wuttke, Matthias A1 - Kirsten, Holger A1 - Sieber, Karsten B A1 - Qiu, Chengxiang A1 - Gorski, Mathias A1 - Yu, Zhi A1 - Giri, Ayush A1 - Sveinbjornsson, Gardar A1 - Li, Man A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - O'Connor, Luke J A1 - Prins, Bram A1 - Nutile, Teresa A1 - Noce, Damia A1 - Akiyama, Masato A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - van der Most, Peter J A1 - Horn, Katrin A1 - Xu, Yizhe A1 - Fuchsberger, Christian A1 - Sedaghat, Sanaz A1 - Afaq, Saima A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Cusi, Daniele A1 - Felicita, Sala Cinzia A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Devuyst, Olivier A1 - Dittrich, Katalin A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Gansevoort, Ron T A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Holm, Hilma A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Lewis, Raychel M A1 - Ingelsson, Erik A1 - Jakobsdottir, Johanna A1 - Jonsdottir, Ingileif A1 - Jonsson, Helgi A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerr, Shona M A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - La Bianca, Martina A1 - Lange, Leslie A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liu, Jun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - O'Donnell, Christopher J A1 - Wilson, Otis D A1 - Gaziano, J Michael A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Müller-Nurasyid, Martina A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey R A1 - Olafsson, Isleifur A1 - Padmanabhan, Sandosh A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Peters, Annette A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Preuss, Michael H A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Robino, Antonietta A1 - Rudan, Igor A1 - Krajcoviechova, Alena A1 - Cifkova, Renata A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Shaffer, Christian M A1 - Smith, Albert V A1 - Smith, Blair H A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Tajuddin, Salman M A1 - Teren, Andrej A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thorsteinsdottir, Unnur A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Yang, Qiong A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Bochud, Murielle A1 - Wilson, James G A1 - Pendergrass, Sarah A A1 - Ho, Kevin A1 - Parsa, Afshin A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Böger, Carsten A A1 - Snieder, Harold A1 - Butterworth, Adam S A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Stefansson, Kari A1 - Susztak, Katalin A1 - Scholz, Markus A1 - Heid, Iris M A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Pattaro, Cristian A1 - Woodward, Owen M A1 - Vitart, Veronique A1 - Köttgen, Anna AB -

Elevated 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.

VL - 51 IS - 10 ER - TY - JOUR T1 - Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. JF - Nat Genet Y1 - 2019 A1 - Giri, Ayush A1 - Hellwege, Jacklyn N A1 - Keaton, Jacob M A1 - Park, Jihwan A1 - Qiu, Chengxiang A1 - Warren, Helen R A1 - Torstenson, Eric S A1 - Kovesdy, Csaba P A1 - Sun, Yan V A1 - Wilson, Otis D A1 - Robinson-Cohen, Cassianne A1 - Roumie, Christianne L A1 - Chung, Cecilia P A1 - Birdwell, Kelly A A1 - Damrauer, Scott M A1 - DuVall, Scott L A1 - Klarin, Derek A1 - Cho, Kelly A1 - Wang, Yu A1 - Evangelou, Evangelos A1 - Cabrera, Claudia P A1 - Wain, Louise V A1 - Shrestha, Rojesh A1 - Mautz, Brian S A1 - Akwo, Elvis A A1 - Sargurupremraj, Muralidharan A1 - Debette, Stephanie A1 - Boehnke, Michael A1 - Scott, Laura J A1 - Luan, Jian'an A1 - Zhao, Jing-Hua A1 - Willems, Sara M A1 - Thériault, Sébastien A1 - Shah, Nabi A1 - Oldmeadow, Christopher A1 - Almgren, Peter A1 - Li-Gao, Ruifang A1 - Verweij, Niek A1 - Boutin, Thibaud S A1 - Mangino, Massimo A1 - Ntalla, Ioanna A1 - Feofanova, Elena A1 - Surendran, Praveen A1 - Cook, James P A1 - Karthikeyan, Savita A1 - Lahrouchi, Najim A1 - Liu, Chunyu A1 - Sepúlveda, Nuno A1 - Richardson, Tom G A1 - Kraja, Aldi A1 - Amouyel, Philippe A1 - Farrall, Martin A1 - Poulter, Neil R A1 - Laakso, Markku A1 - Zeggini, Eleftheria A1 - Sever, Peter A1 - Scott, Robert A A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Conen, David A1 - Palmer, Colin Neil Alexander A1 - Attia, John A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Melander, Olle A1 - Mook-Kanamori, Dennis Owen A1 - Harst, Pim van der A1 - Cucca, Francesco A1 - Schlessinger, David A1 - Hayward, Caroline A1 - Spector, Tim D A1 - Jarvelin, Marjo-Riitta A1 - Hennig, Branwen J A1 - Timpson, Nicholas J A1 - Wei, Wei-Qi A1 - Smith, Joshua C A1 - Xu, Yaomin A1 - Matheny, Michael E A1 - Siew, Edward E A1 - Lindgren, Cecilia A1 - Herzig, Karl-Heinz A1 - Dedoussis, George A1 - Denny, Joshua C A1 - Psaty, Bruce M A1 - Howson, Joanna M M A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Gaziano, J Michael A1 - Concato, John A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Velez Edwards, Digna R A1 - Susztak, Katalin A1 - O'Donnell, Christopher J A1 - Hung, Adriana M A1 - Edwards, Todd L AB -

In 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.

VL - 51 IS - 1 ER - TY - JOUR T1 - Trends in Blood Pressure and High-Sensitivity Cardiac Troponin-T with Cardiovascular Disease: The Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2019 A1 - Tehrani, David M A1 - Fan, Wenjun A1 - Nambi, Vijay A1 - Gardin, Julius A1 - Hirsch, Calvin H A1 - Amsterdam, Ezra A1 - deFilippi, Christopher R A1 - Polonsky, Tamar A1 - Wong, Nathan D AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Use of a pooled cohort to impute cardiovascular disease risk factors across the adult life course. JF - Int J Epidemiol Y1 - 2019 A1 - Zeki Al Hazzouri, Adina A1 - Vittinghoff, Eric A1 - Zhang, Yiyi A1 - Pletcher, Mark J A1 - Moran, Andrew E A1 - Bibbins-Domingo, Kirsten A1 - Golden, Sherita H A1 - Yaffe, Kristine AB -

BACKGROUND: 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.

VL - 48 IS - 3 ER - TY - JOUR T1 - {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 Latinos JF - Sci Rep Y1 - 2019 A1 - Sofer, T. A1 - Emery, L. A1 - Jain, D. A1 - Ellis, A. M. A1 - Laurie, C. C. A1 - Allison, M. A. A1 - Lee, J. A1 - Kurniansyah, N. A1 - Kerr, K. F. A1 - Gonz?lez, H. M. A1 - Tarraf, W. A1 - Criqui, M. H. A1 - Lange, L. A. A1 - Palmas, W. R. A1 - Franceschini, N. A1 - Wassel, C. L. AB - Lower 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. VL - 9 ER - TY - JOUR T1 - Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene. JF - J Neuropathol Exp Neurol Y1 - 2020 A1 - Katsumata, Yuriko A1 - Fardo, David W A1 - Bachstetter, Adam D A1 - Artiushin, Sergey C A1 - Wang, Wang-Xia A1 - Wei, Angela A1 - Brzezinski, Lena J A1 - Nelson, Bela G A1 - Huang, Qingwei A1 - Abner, Erin L A1 - Anderson, Sonya A1 - Patel, Indumati A1 - Shaw, Benjamin C A1 - Price, Douglas A A1 - Niedowicz, Dana M A1 - Wilcock, Donna W A1 - Jicha, Gregory A A1 - Neltner, Janna H A1 - Van Eldik, Linda J A1 - Estus, Steven A1 - Nelson, Peter T KW - Adaptor Protein Complex 2 KW - Adaptor Protein Complex alpha Subunits KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Autopsy KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Minisatellite Repeats KW - Mucin-6 KW - Neurofibrillary Tangles KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - TDP-43 Proteinopathies AB -

We 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.

VL - 79 IS - 1 ER - TY - JOUR T1 - Association of CD14 with incident dementia and markers of brain aging and injury. JF - Neurology Y1 - 2020 A1 - Pase, Matthew P A1 - Himali, Jayandra J A1 - Beiser, Alexa S A1 - DeCarli, Charles A1 - McGrath, Emer R A1 - Satizabal, Claudia L A1 - Aparicio, Hugo J A1 - Adams, Hieab H H A1 - Reiner, Alexander P A1 - Longstreth, W T A1 - Fornage, Myriam A1 - Tracy, Russell P A1 - Lopez, Oscar A1 - Psaty, Bruce M A1 - Levy, Daniel A1 - Seshadri, Sudha A1 - Bis, Joshua C AB -

OBJECTIVE: 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.

VL - 94 IS - 3 ER - TY - JOUR T1 - Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study. JF - J Thromb Haemost Y1 - 2020 A1 - Tang, Weihong A1 - Stimson, Mary Rachel A1 - Basu, Saonli A1 - Heckbert, Susan R A1 - Cushman, Mary A1 - Pankow, James S A1 - Folsom, Aaron R A1 - Pankratz, Nathan AB -

BACKGROUND: 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.

VL - 18 IS - 2 ER - TY - JOUR T1 - {Cerebral small vessel disease genomics and its implications across the lifespan JF - Nat Commun Y1 - 2020 A1 - Sargurupremraj, M. A1 - Suzuki, H. A1 - Jian, X. A1 - Sarnowski, C. A1 - Evans, T. E. A1 - Bis, J. C. A1 - Eiriksdottir, G. A1 - Sakaue, S. A1 - Terzikhan, N. A1 - Habes, M. A1 - Zhao, W. A1 - Armstrong, N. J. A1 - Hofer, E. A1 - Yanek, L. R. A1 - Hagenaars, S. P. A1 - Kumar, R. B. A1 - van den Akker, E. B. A1 - McWhirter, R. E. A1 - Trompet, S. A1 - Mishra, A. A1 - Saba, Y. A1 - Satizabal, C. L. A1 - Beaudet, G. A1 - Petit, L. A1 - Tsuchida, A. A1 - Zago, L. A1 - Schilling, S. A1 - Sigurdsson, S. A1 - Gottesman, R. F. A1 - Lewis, C. E. A1 - Aggarwal, N. T. A1 - Lopez, O. L. A1 - Smith, J. A. A1 - Vald?s Hern?ndez, M. C. A1 - van der Grond, J. A1 - Wright, M. J. A1 - Knol, M. J. A1 - D?rr, M. A1 - Thomson, R. J. A1 - Bordes, C. A1 - Le Grand, Q. A1 - Duperron, M. G. A1 - Smith, A. V. A1 - Knopman, D. S. A1 - Schreiner, P. J. A1 - Evans, D. A. A1 - Rotter, J. I. A1 - Beiser, A. S. A1 - Maniega, S. M. A1 - Beekman, M. A1 - Trollor, J. A1 - Stott, D. J. A1 - Vernooij, M. W. A1 - Wittfeld, K. A1 - Niessen, W. J. A1 - Soumar?, A. A1 - Boerwinkle, E. A1 - Sidney, S. A1 - Turner, S. T. A1 - Davies, G. A1 - Thalamuthu, A. A1 - V?lker, U. A1 - van Buchem, M. A. A1 - Bryan, R. N. A1 - Dupuis, J. A1 - Bastin, M. E. A1 - Ames, D. A1 - Teumer, A. A1 - Amouyel, P. A1 - Kwok, J. B. A1 - B?low, R. A1 - Deary, I. J. A1 - Schofield, P. R. A1 - Brodaty, H. A1 - Jiang, J. A1 - Tabara, Y. A1 - Setoh, K. A1 - Miyamoto, S. A1 - Yoshida, K. A1 - Nagata, M. A1 - Kamatani, Y. A1 - Matsuda, F. A1 - Psaty, B. M. A1 - Bennett, D. A. A1 - De Jager, P. L. A1 - Mosley, T. H. A1 - Sachdev, P. S. A1 - Schmidt, R. A1 - Warren, H. R. A1 - Evangelou, E. A1 - Tr?gou?t, D. A. A1 - Ikram, M. A. A1 - Wen, W. A1 - DeCarli, C. A1 - Srikanth, V. K. A1 - Jukema, J. W. A1 - Slagboom, E. P. A1 - Kardia, S. L. R. A1 - Okada, Y. A1 - Mazoyer, B. A1 - Wardlaw, J. M. A1 - Nyquist, P. A. A1 - Mather, K. A. A1 - Grabe, H. J. A1 - Schmidt, H. A1 - van Duijn, C. M. A1 - Gudnason, V. A1 - Longstreth, W. T. A1 - Launer, L. J. A1 - Lathrop, M. A1 - Seshadri, S. A1 - Tzourio, C. A1 - Adams, H. H. A1 - Matthews, P. M. A1 - Fornage, M. A1 - Debette, S. A1 - Amouyel, P. A1 - de Andrade, M. A1 - Basu, S. A1 - Berr, C. A1 - Brody, J. A. A1 - Chasman, D. I. A1 - Dartigues, J. F. A1 - Folsom, A. R. A1 - Germain, M. A1 - de Haan, H. A1 - Heit, J. A1 - Houwing-Duitermaat, J. A1 - Kabrhel, C. A1 - Kraft, P. A1 - Legal, G. A1 - Lindstr?m, S. A1 - Monajemi, R. A1 - Morange, P. E. A1 - Psaty, B. M. A1 - Reitsma, P. H. A1 - Ridker, P. M. A1 - Rose, L. M. A1 - Rosendaal, F. R. A1 - Saut, N. A1 - Slagboom, E. A1 - Smadja, D. A1 - Smith, N. L. A1 - Suchon, P. A1 - Tang, W. A1 - Taylor, K. D. A1 - Tr?gou?t, D. A. A1 - Tzourio, C. A1 - de Visser, M. C. H. A1 - van Hylckama Vlieg, A. A1 - Weng, L. C. A1 - Wiggins, K. L. A1 - Gormley, P. A1 - Anttila, V. A1 - Winsvold, B. S. A1 - Palta, P. A1 - Esko, T. A1 - Pers, T. H. A1 - Farh, K. H. A1 - Cuenca-Leon, E. A1 - Muona, M. A1 - Furlotte, N. A. A1 - Kurth, T. A1 - Ingason, A. A1 - McMahon, G. A1 - Ligthart, L. A1 - Terwindt, G. M. A1 - Kallela, M. A1 - Freilinger, T. M. A1 - Ran, C. A1 - Gordon, S. G. A1 - Stam, A. H. A1 - Steinberg, S. A1 - Borck, G. A1 - Koiranen, M. A1 - Quaye, L. A1 - Adams, H. H. H. A1 - Lehtim?ki, T. A1 - Sarin, A. P. A1 - Wedenoja, J. A1 - Hinds, D. A. A1 - Buring, J. E. A1 - Sch?rks, M. A1 - Ridker, P. M. A1 - Gudlaug Hrafnsdottir, M. A1 - Stefansson, H. A1 - Ring, S. M. A1 - Hottenga, J. J. A1 - Penninx, B. W. J. H. A1 - F?rkkil?, M. A1 - Artto, V. A1 - Kaunisto, M. A1 - Veps?l?inen, S. A1 - Malik, R. A1 - Heath, A. C. A1 - Madden, P. A. F. A1 - Martin, N. G. A1 - Montgomery, G. W. A1 - Kurki, M. A1 - Kals, M. A1 - M?gi, R. A1 - P?rn, K. A1 - H?m?l?inen, E. A1 - Huang, H. A1 - Byrnes, A. E. A1 - Franke, L. A1 - Huang, J. A1 - Stergiakouli, E. A1 - Lee, P. H. A1 - Sandor, C. A1 - Webber, C. A1 - Cader, Z. A1 - Muller-Myhsok, B. A1 - Schreiber, S. A1 - Meitinger, T. A1 - Eriksson, J. G. A1 - Salomaa, V. A1 - Heikkil?, K. A1 - Loehrer, E. A1 - Uitterlinden, A. G. A1 - Hofman, A. A1 - van Duijn, C. M. A1 - Cherkas, L. A1 - Pedersen, L. M. A1 - Stubhaug, A. A1 - Nielsen, C. S. A1 - M?nnikk?, M. A1 - Mihailov, E. A1 - Milani, L. A1 - G?bel, H. A1 - Esserlind, A. L. A1 - Francke Christensen, A. A1 - Folkmann Hansen, T. A1 - Werge, T. A1 - Kaprio, J. A1 - Aromaa, A. J. A1 - Raitakari, O. A1 - Ikram, M. A. A1 - Spector, T. A1 - J?rvelin, M. R. A1 - Metspalu, A. A1 - Kubisch, C. A1 - Strachan, D. P. A1 - Ferrari, M. D. A1 - Belin, A. C. A1 - Dichgans, M. A1 - Wessman, M. A1 - van den Maagdenberg, A. M. J. M. A1 - Zwart, J. A. A1 - Boomsma, D. I. A1 - Davey Smith, G. A1 - Stefansson, K. A1 - Eriksson, N. A1 - Daly, M. J. A1 - Neale, B. M. A1 - Olesen, J. A1 - Chasman, D. I. A1 - Nyholt, D. R. A1 - Palotie, A. AB - White 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. VL - 11 ER - TY - JOUR T1 - Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study. JF - JCI Insight Y1 - 2020 A1 - Patel, Ravi B A1 - Delaney, Joseph A A1 - Hu, Mo A1 - Patel, Harnish A1 - Cheng, Jeanette A1 - Gottdiener, John A1 - Kizer, Jorge R A1 - Marcus, Gregory M A1 - Turakhia, Mintu P A1 - Deo, Rajat A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Shah, Sanjiv J AB -

BACKGROUND: 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.

VL - 5 IS - 19 ER - TY - JOUR T1 - Cholesterol Variability and Cranial Magnetic Resonance Imaging Findings in Older Adults: The Cardiovascular Health Study. JF - Stroke Y1 - 2020 A1 - Kalani, Rizwan A1 - Bartz, Traci M A1 - Suchy-Dicey, Astrid A1 - Elkind, Mitchell S V A1 - Psaty, Bruce M A1 - Leung, Lester Y A1 - Rice, Kenneth A1 - Tirschwell, David A1 - Longstreth, W T AB -

Background 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.

VL - 51 IS - 1 ER - TY - JOUR T1 - Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. JF - Lancet Respir Med Y1 - 2020 A1 - Moll, Matthew A1 - Sakornsakolpat, Phuwanat A1 - Shrine, Nick A1 - Hobbs, Brian D A1 - DeMeo, Dawn L A1 - John, Catherine A1 - Guyatt, Anna L A1 - McGeachie, Michael J A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Lahousse, Lies A1 - Wijnant, Sara R A A1 - Brusselle, Guy A1 - Meyers, Deborah A A1 - Bleecker, Eugene R A1 - Li, Xingnan A1 - Tal-Singer, Ruth A1 - Manichaikul, Ani A1 - Rich, Stephen S A1 - Won, Sungho A1 - Kim, Woo Jin A1 - Do, Ah Ra A1 - Washko, George R A1 - Barr, R Graham A1 - Psaty, Bruce M A1 - Bartz, Traci M A1 - Hansel, Nadia N A1 - Barnes, Kathleen A1 - Hokanson, John E A1 - Crapo, James D A1 - Lynch, David A1 - Bakke, Per A1 - Gulsvik, Amund A1 - Hall, Ian P A1 - Wain, Louise A1 - Weiss, Scott T A1 - Silverman, Edwin K A1 - Dudbridge, Frank A1 - Tobin, Martin D A1 - Cho, Michael H KW - Adult KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Pulmonary Disease, Chronic Obstructive KW - Risk Factors KW - Vital Capacity AB -

BACKGROUND: 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.

VL - 8 IS - 7 ER - TY - JOUR T1 - Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study. JF - PLoS One Y1 - 2020 A1 - Rohmann, Jessica L A1 - Longstreth, W T A1 - Cushman, Mary A1 - Fitzpatrick, Annette L A1 - Heckbert, Susan R A1 - Rice, Kenneth A1 - Rosendaal, Frits R A1 - Sitlani, Colleen M A1 - Psaty, Bruce M A1 - Siegerink, Bob KW - Aged KW - Blood Coagulation KW - Cognition KW - Cross-Sectional Studies KW - Factor VIII KW - Female KW - Humans KW - Logistic Models KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Mental Status and Dementia Tests KW - Up-Regulation KW - White Matter AB -

OBJECTIVE: 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.

VL - 15 IS - 11 ER - TY - JOUR T1 - The Difference Between Cystatin C and Creatinine-Based Estimated GFR and Incident Frailty: An Analysis of the Cardiovascular Health Study (CHS). JF - Am J Kidney Dis Y1 - 2020 A1 - Potok, O Alison A1 - Phil, Ronit Katz D A1 - Bansal, Nisha A1 - Siscovick, David S A1 - Odden, Michelle A1 - Ix, Joachim H A1 - Shlipak, Michael G A1 - Rifkin, Dena E ER - TY - JOUR T1 - {Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals JF - Nat Genet Y1 - 2020 A1 - Surendran, P. A1 - Feofanova, E. V. A1 - Lahrouchi, N. A1 - Ntalla, I. A1 - Karthikeyan, S. A1 - Cook, J. A1 - Chen, L. A1 - Mifsud, B. A1 - Yao, C. A1 - Kraja, A. T. A1 - Cartwright, J. H. A1 - Hellwege, J. N. A1 - Giri, A. A1 - Tragante, V. A1 - Thorleifsson, G. A1 - Liu, D. J. A1 - Prins, B. P. A1 - Stewart, I. D. A1 - Cabrera, C. P. A1 - Eales, J. M. A1 - Akbarov, A. A1 - Auer, P. L. A1 - Bielak, L. F. A1 - Bis, J. C. A1 - Braithwaite, V. 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A1 - Varga, T. V. A1 - Velez Edwards, D. R. A1 - Veronesi, G. A1 - Weiss, S. A1 - Willems, S. M. A1 - Yao, J. A1 - Young, R. A1 - Yu, B. A1 - Zhang, W. A1 - Zhao, J. H. A1 - Zhao, W. A1 - Zhao, W. A1 - Evangelou, E. A1 - Aeschbacher, S. A1 - Asllanaj, E. A1 - Blankenberg, S. A1 - Bonnycastle, L. L. A1 - Bork-Jensen, J. A1 - Brandslund, I. A1 - Braund, P. S. A1 - Burgess, S. A1 - Cho, K. A1 - Christensen, C. A1 - Connell, J. A1 - Mutsert, R. A1 - Dominiczak, A. F. A1 - D?rr, M. A1 - Eiriksdottir, G. A1 - Farmaki, A. E. A1 - Gaziano, J. M. A1 - Grarup, N. A1 - Grove, M. L. A1 - Hallmans, G. A1 - Hansen, T. A1 - Have, C. T. A1 - Heiss, G. A1 - J?rgensen, M. E. A1 - Jousilahti, P. A1 - Kajantie, E. A1 - Kamat, M. A1 - K?r?j?m?ki, A. A1 - Karpe, F. A1 - Koistinen, H. A. A1 - Kovesdy, C. P. A1 - Kuulasmaa, K. A1 - Laatikainen, T. A1 - Lannfelt, L. A1 - Lee, I. T. A1 - Lee, W. J. A1 - Linneberg, A. A1 - Martin, L. W. A1 - Moitry, M. A1 - Nadkarni, G. A1 - Neville, M. J. A1 - Palmer, C. N. A. A1 - Papanicolaou, G. J. A1 - Pedersen, O. A1 - Peters, J. A1 - Poulter, N. A1 - Rasheed, A. A1 - Rasmussen, K. L. A1 - Rayner, N. W. A1 - M?gi, R. A1 - Renstr?m, F. A1 - Rettig, R. A1 - Rossouw, J. A1 - Schreiner, P. J. A1 - Sever, P. S. A1 - Sigurdsson, E. L. A1 - Skaaby, T. A1 - Sun, Y. V. A1 - Sundstrom, J. A1 - Thorgeirsson, G. A1 - Esko, T. A1 - Trabetti, E. A1 - Tsao, P. S. A1 - Tuomi, T. A1 - Turner, S. T. A1 - Tzoulaki, I. A1 - Vaartjes, I. A1 - Vergnaud, A. C. A1 - Willer, C. J. A1 - Wilson, P. W. F. A1 - Witte, D. R. A1 - Yonova-Doing, E. A1 - Zhang, H. A1 - Aliya, N. A1 - Almgren, P. A1 - Amouyel, P. A1 - Asselbergs, F. W. A1 - Barnes, M. R. A1 - Blakemore, A. I. A1 - Boehnke, M. A1 - Bots, M. L. A1 - Bottinger, E. P. A1 - Buring, J. E. A1 - Chambers, J. C. A1 - Chen, Y. I. A1 - Chowdhury, R. A1 - Conen, D. A1 - Correa, A. A1 - Davey Smith, G. A1 - Boer, R. A. A1 - Deary, I. J. A1 - Dedoussis, G. A1 - Deloukas, P. A1 - Di Angelantonio, E. A1 - Elliott, P. A1 - Felix, S. B. A1 - Ferri?res, J. A1 - Ford, I. A1 - Fornage, M. A1 - Franks, P. W. A1 - Franks, S. A1 - Frossard, P. A1 - Gambaro, G. A1 - Gaunt, T. R. A1 - Groop, L. A1 - Gudnason, V. A1 - Harris, T. B. A1 - Hayward, C. A1 - Hennig, B. J. A1 - Herzig, K. H. A1 - Ingelsson, E. A1 - Tuomilehto, J. A1 - J?rvelin, M. R. A1 - Jukema, J. W. A1 - Kardia, S. L. R. A1 - Kee, F. A1 - Kooner, J. S. A1 - Kooperberg, C. A1 - Launer, L. J. A1 - Lind, L. A1 - Loos, R. J. F. A1 - Majumder, A. A. S. A1 - Laakso, M. A1 - McCarthy, M. I. A1 - Melander, O. A1 - Mohlke, K. L. A1 - Murray, A. D. A1 - Nordestgaard, B. G. A1 - Orho-Melander, M. A1 - Packard, C. J. A1 - Padmanabhan, S. A1 - Palmas, W. A1 - Polasek, O. A1 - Porteous, D. J. A1 - Prentice, A. M. A1 - Province, M. A. A1 - Relton, C. L. A1 - Rice, K. A1 - Ridker, P. M. A1 - Rolandsson, O. A1 - Rosendaal, F. R. A1 - Rotter, J. I. A1 - Rudan, I. A1 - Salomaa, V. A1 - Samani, N. J. A1 - Sattar, N. A1 - Sheu, W. H. A1 - Smith, B. H. A1 - Soranzo, N. A1 - Spector, T. D. A1 - Starr, J. M. A1 - Sebert, S. A1 - Taylor, K. D. A1 - Lakka, T. A. A1 - Timpson, N. J. A1 - Tobin, M. D. A1 - van der Harst, P. A1 - van der Meer, P. A1 - Ramachandran, V. S. A1 - Verweij, N. A1 - Virtamo, J. A1 - V?lker, U. A1 - Weir, D. R. A1 - Zeggini, E. A1 - Charchar, F. J. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Tomaszewski, M. A1 - Butterworth, A. S. A1 - Caulfield, M. J. A1 - Danesh, J. A1 - Edwards, T. L. A1 - Holm, H. A1 - Hung, A. M. A1 - Lindgren, C. M. A1 - Liu, C. A1 - Manning, A. K. A1 - Morris, A. P. A1 - Morrison, A. C. A1 - O'Donnell, C. J. A1 - Psaty, B. M. A1 - Saleheen, D. A1 - Stefansson, K. A1 - Boerwinkle, E. A1 - Chasman, D. I. A1 - Levy, D. A1 - Newton-Cheh, C. A1 - Munroe, P. B. A1 - Howson, J. M. M. A1 - de Boer, R. A. A1 - van der Harst, P. A1 - van der Meer, P. A1 - Verweij, N. A1 - Butterworth, A. S. A1 - Danesh, J. A1 - Langenberg, C. A1 - Deloukas, P. A1 - McCarthy, M. I. A1 - Franks, P. W. A1 - Rolandsson, O. A1 - Wareham, N. J. A1 - Prins, B. P. A1 - Zeggini, E. A1 - Hellwege, J. N. A1 - Giri, A. A1 - Edwards, D. R. V. A1 - Cho, K. A1 - Gaziano, J. M. A1 - Kovesdy, C. P. A1 - Sun, Y. V. A1 - Tsao, P. S. A1 - Wilson, P. W. F. A1 - Edwards, T. L. A1 - Hung, A. M. A1 - O'Donnell, C. J. AB - Genetic 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. VL - 52 ER - TY - JOUR T1 - {Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale JF - Nat Genet Y1 - 2020 A1 - Li, X. A1 - Li, Z. A1 - Zhou, H. A1 - Gaynor, S. M. A1 - Liu, Y. A1 - Chen, H. A1 - Sun, R. A1 - Dey, R. A1 - Arnett, D. K. A1 - Aslibekyan, S. A1 - Ballantyne, C. M. A1 - Bielak, L. F. A1 - Blangero, J. A1 - Boerwinkle, E. A1 - Bowden, D. W. A1 - Broome, J. G. A1 - Conomos, M. P. A1 - Correa, A. A1 - Cupples, L. A. A1 - Curran, J. E. A1 - Freedman, B. I. A1 - Guo, X. A1 - Hindy, G. A1 - Irvin, M. R. A1 - Kardia, S. L. R. A1 - Kathiresan, S. A1 - Khan, A. T. A1 - Kooperberg, C. L. A1 - Laurie, C. C. A1 - Liu, X. S. A1 - Mahaney, M. C. A1 - Manichaikul, A. W. A1 - Martin, L. W. A1 - Mathias, R. A. A1 - McGarvey, S. T. A1 - Mitchell, B. D. A1 - Montasser, M. E. A1 - Moore, J. E. A1 - Morrison, A. C. A1 - O'Connell, J. R. A1 - Palmer, N. D. A1 - Pampana, A. A1 - Peralta, J. M. A1 - Peyser, P. A. A1 - Psaty, B. M. A1 - Redline, S. A1 - Rice, K. M. A1 - Rich, S. S. A1 - Smith, J. A. A1 - Tiwari, H. K. A1 - Tsai, M. Y. A1 - Vasan, R. S. A1 - Wang, F. F. A1 - Weeks, D. E. A1 - Weng, Z. A1 - Wilson, J. G. A1 - Yanek, L. R. A1 - Neale, B. M. A1 - Sunyaev, S. R. A1 - Abecasis, G. R. A1 - Rotter, J. I. A1 - Willer, C. J. A1 - Peloso, G. M. A1 - Natarajan, P. A1 - Lin, X. A1 - Abe, N. A1 - Abecasis, G. R. A1 - Aguet, F. A1 - Albert, C. A1 - Almasy, L. A1 - Alonso, A. A1 - Ament, S. A1 - Anderson, P. A1 - Anugu, P. A1 - Applebaum-Bowden, D. A1 - Ardlie, K. A1 - Arking, D. A1 - Arnett, D. K. A1 - Ashley-Koch, A. A1 - Aslibekyan, S. A1 - Assimes, T. A1 - Auer, P. A1 - Avramopoulos, D. A1 - Barnard, J. A1 - Barnes, K. A1 - Barr, R. G. A1 - Barron-Casella, E. A1 - Barwick, L. A1 - Beaty, T. A1 - Beck, G. A1 - Becker, D. A1 - Becker, L. A1 - Beer, R. A1 - Beitelshees, A. A1 - Benjamin, E. A1 - Benos, T. A1 - Bezerra, M. A1 - Bielak, L. F. A1 - Bis, J. A1 - Blackwell, T. A1 - Blangero, J. A1 - Boerwinkle, E. A1 - Bowden, D. W. A1 - Bowler, R. A1 - Brody, J. A1 - Broeckel, U. A1 - Broome, J. G. A1 - Bunting, K. A1 - Burchard, E. A1 - Bustamante, C. A1 - Buth, E. A1 - Cade, B. A1 - Cardwell, J. A1 - Carey, V. A1 - Carty, C. A1 - Casaburi, R. A1 - Casella, J. A1 - Castaldi, P. A1 - Chaffin, M. A1 - Chang, C. A1 - Chang, Y. C. A1 - Chasman, D. A1 - Chavan, S. A1 - Chen, B. J. A1 - Chen, W. M. A1 - Chen, Y. I. A1 - Cho, M. A1 - Choi, S. H. A1 - Chuang, L. M. A1 - Chung, M. A1 - Chung, R. H. A1 - Clish, C. A1 - Comhair, S. A1 - Conomos, M. P. A1 - Cornell, E. A1 - Correa, A. A1 - Crandall, C. A1 - Crapo, J. A1 - Cupples, L. A. A1 - Curran, J. E. A1 - Curtis, J. A1 - Custer, B. A1 - Damcott, C. A1 - Darbar, D. A1 - Das, S. A1 - David, S. A1 - Davis, C. A1 - Daya, M. A1 - de Andrade, M. A1 - Fuentes, L. L. A1 - DeBaun, M. A1 - Deka, R. A1 - DeMeo, D. A1 - Devine, S. A1 - Duan, Q. A1 - Duggirala, R. A1 - Durda, J. P. A1 - Dutcher, S. A1 - Eaton, C. A1 - Ekunwe, L. A1 - El Boueiz, A. A1 - Ellinor, P. A1 - Emery, L. A1 - Erzurum, S. A1 - Farber, C. A1 - Fingerlin, T. A1 - Flickinger, M. A1 - Fornage, M. A1 - Franceschini, N. A1 - Frazar, C. A1 - Fu, M. A1 - Fullerton, S. M. A1 - Fulton, L. A1 - Gabriel, S. A1 - Gan, W. A1 - Gao, S. A1 - Gao, Y. A1 - Gass, M. A1 - Gelb, B. A1 - Geng, X. P. A1 - Geraci, M. A1 - Germer, S. A1 - Gerszten, R. A1 - Ghosh, A. A1 - Gibbs, R. A1 - Gignoux, C. A1 - Gladwin, M. A1 - Glahn, D. A1 - Gogarten, S. A1 - Gong, D. W. A1 - Goring, H. A1 - Graw, S. A1 - Grine, D. A1 - Gu, C. C. A1 - Guan, Y. A1 - Guo, X. A1 - Gupta, N. A1 - Haessler, J. A1 - Hall, M. A1 - Harris, D. A1 - Hawley, N. L. A1 - He, J. A1 - Heckbert, S. A1 - Hernandez, R. A1 - Herrington, D. A1 - Hersh, C. A1 - Hidalgo, B. A1 - Hixson, J. A1 - Hobbs, B. A1 - Hokanson, J. A1 - Hong, E. A1 - Hoth, K. A1 - Hsiung, C. A. A1 - Hung, Y. J. A1 - Huston, H. A1 - Hwu, C. M. A1 - Irvin, M. R. A1 - Jackson, R. A1 - Jain, D. A1 - Jaquish, C. A1 - Jhun, M. A. A1 - Johnsen, J. A1 - Johnson, A. A1 - Johnson, C. A1 - Johnston, R. A1 - Jones, K. A1 - Kang, H. M. A1 - Kaplan, R. A1 - Kardia, S. L. R. A1 - Kathiresan, S. A1 - Kelly, S. A1 - Kenny, E. A1 - Kessler, M. A1 - Khan, A. T. A1 - Kim, W. A1 - Kinney, G. A1 - Konkle, B. A1 - Kooperberg, C. L. A1 - Kramer, H. A1 - Lange, C. A1 - Lange, E. A1 - Lange, L. A1 - Laurie, C. C. A1 - Laurie, C. A1 - LeBoff, M. A1 - Lee, J. A1 - Lee, S. S. A1 - Lee, W. J. A1 - LeFaive, J. A1 - Levine, D. A1 - Levy, D. A1 - Lewis, J. A1 - Li, X. A1 - Li, Y. A1 - Lin, H. A1 - Lin, H. A1 - Lin, K. H. A1 - Lin, X. A1 - Liu, S. A1 - Liu, Y. A1 - Liu, Y. A1 - Loos, R. J. F. A1 - Lubitz, S. A1 - Lunetta, K. A1 - Luo, J. A1 - Mahaney, M. C. A1 - Make, B. A1 - Manichaikul, A. W. A1 - Manson, J. A1 - Margolin, L. A1 - Martin, L. W. A1 - Mathai, S. A1 - Mathias, R. A. A1 - May, S. A1 - McArdle, P. A1 - McDonald, M. L. A1 - McFarland, S. A1 - McGarvey, S. T. A1 - McGoldrick, D. A1 - McHugh, C. A1 - Mei, H. A1 - Mestroni, L. A1 - Meyers, D. A. A1 - Mikulla, J. A1 - Min, N. A1 - Minear, M. A1 - Minster, R. L. A1 - Mitchell, B. D. A1 - Moll, M. A1 - Montasser, M. E. A1 - Montgomery, C. A1 - Moscati, A. A1 - Musani, S. A1 - Mwasongwe, S. A1 - Mychaleckyj, J. C. A1 - Nadkarni, G. A1 - Naik, R. A1 - Naseri, T. A1 - Natarajan, P. A1 - Nekhai, S. A1 - Nelson, S. C. A1 - Neltner, B. A1 - Nickerson, D. A1 - North, K. A1 - O'Connell, J. R. A1 - O'Connor, T. A1 - Ochs-Balcom, H. A1 - Paik, D. A1 - Palmer, N. D. A1 - Pankow, J. A1 - Papanicolaou, G. A1 - Parsa, A. A1 - Peralta, J. M. A1 - Perez, M. A1 - Perry, J. A1 - Peters, U. A1 - Peyser, P. A. A1 - Phillips, L. S. A1 - Pollin, T. A1 - Post, W. A1 - Becker, J. P. A1 - Boorgula, M. P. A1 - Preuss, M. A1 - Psaty, B. M. A1 - Qasba, P. A1 - Qiao, D. A1 - Qin, Z. A1 - Rafaels, N. A1 - Raffield, L. A1 - Vasan, R. S. A1 - Rao, D. C. A1 - Rasmussen-Torvik, L. A1 - Ratan, A. A1 - Redline, S. A1 - Reed, R. A1 - Regan, E. A1 - Reiner, A. A1 - Reupena, M. S. A1 - Rice, K. M. A1 - Rich, S. S. A1 - Roden, D. A1 - Roselli, C. A1 - Rotter, J. I. A1 - Ruczinski, I. A1 - Russell, P. A1 - Ruuska, S. A1 - Ryan, K. A1 - Sabino, E. C. A1 - Saleheen, D. A1 - Salimi, S. A1 - Salzberg, S. A1 - Sandow, K. A1 - Sankaran, V. G. A1 - Scheller, C. A1 - Schmidt, E. A1 - Schwander, K. A1 - Schwartz, D. A1 - Sciurba, F. A1 - Seidman, C. A1 - Seidman, J. A1 - Sheehan, V. A1 - Sherman, S. L. A1 - Shetty, A. A1 - Shetty, A. A1 - Sheu, W. H. A1 - Shoemaker, M. B. A1 - Silver, B. A1 - Silverman, E. A1 - Smith, J. A. A1 - Smith, J. A1 - Smith, N. A1 - Smith, T. A1 - Smoller, S. A1 - Snively, B. A1 - Snyder, M. A1 - Sofer, T. A1 - Sotoodehnia, N. A1 - Stilp, A. M. A1 - Storm, G. A1 - Streeten, E. A1 - Su, J. L. A1 - Sung, Y. J. A1 - Sylvia, J. A1 - Szpiro, A. A1 - Sztalryd, C. A1 - Taliun, D. A1 - Tang, H. A1 - Taub, M. A1 - Taylor, K. D. A1 - Taylor, M. A1 - Taylor, S. A1 - Telen, M. A1 - Thornton, T. A. A1 - Threlkeld, M. A1 - Tinker, L. A1 - Tirschwell, D. A1 - Tishkoff, S. A1 - Tiwari, H. K. A1 - Tong, C. A1 - Tracy, R. A1 - Tsai, M. Y. A1 - Vaidya, D. A1 - Van Den Berg, D. A1 - VandeHaar, P. A1 - Vrieze, S. A1 - Walker, T. A1 - Wallace, R. A1 - Walts, A. A1 - Wang, F. F. A1 - Wang, H. A1 - Watson, K. A1 - Weeks, D. E. A1 - Weir, B. A1 - Weiss, S. A1 - Weng, L. C. A1 - Wessel, J. A1 - Willer, C. J. A1 - Williams, K. A1 - Williams, L. K. A1 - Wilson, C. A1 - Wilson, J. G. A1 - Wong, Q. A1 - Wu, J. A1 - Xu, H. A1 - Yanek, L. R. A1 - Yang, I. A1 - Yang, R. A1 - Zaghloul, N. A1 - Zekavat, M. A1 - Zhang, Y. A1 - Zhao, S. X. A1 - Zhao, W. A1 - Zhi, D. A1 - Zhou, X. A1 - Zhu, X. A1 - Zody, M. A1 - Zoellner, S. A1 - Abdalla, M. A1 - Abecasis, G. R. A1 - Arnett, D. K. A1 - Aslibekyan, S. A1 - Assimes, T. A1 - Atkinson, E. A1 - Ballantyne, C. M. A1 - Beitelshees, A. A1 - Bielak, L. F. A1 - Bis, J. A1 - Bodea, C. A1 - Boerwinkle, E. A1 - Bowden, D. W. A1 - Brody, J. A1 - Cade, B. A1 - Carlson, J. A1 - Chang, I. S. A1 - Chen, Y. I. A1 - Chun, S. A1 - Chung, R. H. A1 - Conomos, M. P. A1 - Correa, A. A1 - Cupples, L. A. A1 - Damcott, C. A1 - de Vries, P. A1 - Do, R. A1 - Elliott, A. A1 - Fu, M. A1 - Ganna, A. A1 - Gong, D. W. A1 - Graham, S. A1 - Haas, M. A1 - Haring, B. A1 - He, J. A1 - Heckbert, S. A1 - Himes, B. A1 - Hixson, J. A1 - Irvin, M. R. A1 - Jain, D. A1 - Jarvik, G. A1 - Jhun, M. A. A1 - Jiang, J. A1 - Jun, G. A1 - Kalyani, R. A1 - Kardia, S. L. R. A1 - Kathiresan, S. A1 - Khera, A. A1 - Klarin, D. A1 - Kooperberg, C. L. A1 - Kral, B. A1 - Lange, L. A1 - Laurie, C. C. A1 - Laurie, C. A1 - Lemaitre, R. A1 - Li, Z. A1 - Li, X. A1 - Lin, X. A1 - Mahaney, M. C. A1 - Manichaikul, A. W. A1 - Martin, L. W. A1 - Mathias, R. A. A1 - Mathur, R. A1 - McGarvey, S. T. A1 - McHugh, C. A1 - McLenithan, J. A1 - Mikulla, J. A1 - Mitchell, B. D. A1 - Montasser, M. E. A1 - Moran, A. A1 - Morrison, A. C. A1 - Nakao, T. A1 - Natarajan, P. A1 - Nickerson, D. A1 - North, K. A1 - O'Connell, J. R. A1 - O'Donnell, C. A1 - Palmer, N. D. A1 - Pampana, A. A1 - Patel, A. A1 - Peloso, G. M. A1 - Perry, J. A1 - Peters, U. A1 - Peyser, P. A. A1 - Pirruccello, J. A1 - Pollin, T. A1 - Preuss, M. A1 - Psaty, B. M. A1 - Rao, D. C. A1 - Redline, S. A1 - Reed, R. A1 - Reiner, A. A1 - Rich, S. S. A1 - Rosenthal, S. A1 - Rotter, J. I. A1 - Schoenberg, J. A1 - Selvaraj, M. S. A1 - Sheu, W. H. A1 - Smith, J. A. A1 - Sofer, T. A1 - Stilp, A. M. A1 - Sunyaev, S. R. A1 - Surakka, I. A1 - Sztalryd, C. A1 - Tang, H. A1 - Taylor, K. D. A1 - Tsai, M. Y. A1 - Uddin, M. M. A1 - Urbut, S. A1 - Verbanck, M. A1 - Von Holle, A. A1 - Wang, H. A1 - Wang, F. F. A1 - Wiggins, K. A1 - Willer, C. J. A1 - Wilson, J. G. A1 - Wolford, B. A1 - Xu, H. A1 - Yanek, L. R. A1 - Zaghloul, N. A1 - Zekavat, M. A1 - Zhang, J. AB - Large-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. VL - 52 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. JF - Mol Psychiatry Y1 - 2020 A1 - de Las Fuentes, Lisa A1 - Sung, Yun Ju A1 - Noordam, Raymond A1 - Winkler, Thomas A1 - Feitosa, Mary F A1 - Schwander, Karen A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Guo, Xiuqing A1 - Manning, Alisa A1 - Chasman, Daniel I A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Hartwig, Fernando P A1 - Horimoto, A R V R A1 - Li, Changwei A1 - Li-Gao, Ruifang A1 - Liu, Yongmei A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Ntalla, Ioanna A1 - Rankinen, Tuomo A1 - Richard, Melissa A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Vojinovic, Dina A1 - Warren, Helen R A1 - Xuan, Deng A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin-Fang A1 - Chen, Xu A1 - Christensen, Kaare A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Girotto, Giorgia A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Brumat, Marco A1 - Burke, Gregory A1 - Cabrera, Claudia P A1 - Canouil, Mickaël A1 - Chee, Miao Li A1 - Chen, Yii-Der Ida A1 - Cocca, Massimiliano A1 - Connell, John A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Eiriksdottir, Gudny A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Fox, Ervin F A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Kraja, Aldi T A1 - Krieger, J E A1 - Langefeld, Carl D A1 - Li, Yize A1 - Liang, Jingjing A1 - Liewald, David C M A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Lohman, Kurt K A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mook-Kanamori, Dennis O A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Norris, Jill M A1 - O'Connell, Jeff A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Pedersen, Nancy L A1 - Perls, Thomas A1 - Peters, Annette A1 - Petersmann, Astrid A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Raffel, Leslie J A1 - Rice, Treva K A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rueda-Ochoa, Oscar-Leonel A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Schreiner, Pamela J A1 - Shikany, James M A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Teumer, Alexander A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Ende, M Yldau A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Weir, David R A1 - Wen, Wanqing A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Marques-Vidal, Pedro A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Correa, Adolfo A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - Palmas, Walter R A1 - Pereira, A C A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotimi, Charles N A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Rice, Kenneth A1 - Gauderman, W James A1 - Morrison, Alanna C A1 - North, Kari E A1 - Kardia, Sharon L R A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Munroe, Patricia B A1 - Franks, Paul W A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Educational 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.

ER - TY - JOUR T1 - The genetic architecture of the human cerebral cortex JF - Science Y1 - 2020 A1 - Grasby, Katrina L. A1 - Jahanshad, Neda A1 - Painter, Jodie N. A1 - Colodro-Conde, Lucía A1 - Bralten, Janita A1 - Hibar, Derrek P. A1 - Lind, Penelope A. A1 - Pizzagalli, Fabrizio A1 - Ching, Christopher R. K. A1 - McMahon, Mary Agnes B. A1 - Shatokhina, Natalia A1 - Zsembik, Leo C. P. A1 - Thomopoulos, Sophia I. A1 - Zhu, Alyssa H. A1 - Strike, Lachlan T. A1 - Agartz, Ingrid A1 - Alhusaini, Saud A1 - Almeida, Marcio A. A. A1 - Alnæs, Dag A1 - Amlien, Inge K. A1 - Andersson, Micael A1 - Ard, Tyler A1 - Armstrong, Nicola J. A1 - Ashley-Koch, Allison A1 - Atkins, Joshua R. A1 - Bernard, Manon A1 - Brouwer, Rachel M. A1 - Buimer, Elizabeth E. L. A1 - Bülow, Robin A1 - Bürger, Christian A1 - Cannon, Dara M. A1 - Chakravarty, Mallar A1 - Chen, Qiang A1 - Cheung, Joshua W. A1 - Couvy-Duchesne, Baptiste A1 - Dale, Anders M. A1 - Dalvie, Shareefa A1 - de Araujo, Tânia K. A1 - de Zubicaray, Greig I. A1 - de Zwarte, Sonja M. C. A1 - den Braber, Anouk A1 - Doan, Nhat Trung A1 - Dohm, Katharina A1 - Ehrlich, Stefan A1 - Engelbrecht, Hannah-Ruth A1 - Erk, Susanne A1 - Fan, Chun Chieh A1 - Fedko, Iryna O. A1 - Foley, Sonya F. A1 - Ford, Judith M. A1 - Fukunaga, Masaki A1 - Garrett, Melanie E. A1 - Ge, Tian A1 - Giddaluru, Sudheer A1 - Goldman, Aaron L. A1 - Green, Melissa J. A1 - Groenewold, Nynke A. A1 - Grotegerd, Dominik A1 - Gurholt, Tiril P. A1 - Gutman, Boris A. A1 - Hansell, Narelle K. A1 - Harris, Mathew A. A1 - Harrison, Marc B. A1 - Haswell, Courtney C. A1 - Hauser, Michael A1 - Herms, Stefan A1 - Heslenfeld, Dirk J. A1 - Ho, New Fei A1 - Hoehn, David A1 - Hoffmann, Per A1 - Holleran, Laurena A1 - Hoogman, Martine A1 - Hottenga, Jouke-Jan A1 - Ikeda, Masashi A1 - Janowitz, Deborah A1 - Jansen, Iris E. A1 - Jia, Tianye A1 - Jockwitz, Christiane A1 - Kanai, Ryota A1 - Karama, Sherif A1 - Kasperaviciute, Dalia A1 - Kaufmann, Tobias A1 - Kelly, Sinead A1 - Kikuchi, Masataka A1 - Klein, Marieke A1 - Knapp, Michael A1 - Knodt, Annchen R. A1 - Krämer, Bernd A1 - Lam, Max A1 - Lancaster, Thomas M. A1 - Lee, Phil H. A1 - Lett, Tristram A. A1 - Lewis, Lindsay B. A1 - Lopes-Cendes, Iscia A1 - Luciano, Michelle A1 - Macciardi, Fabio A1 - Marquand, Andre F. A1 - Mathias, Samuel R. A1 - Melzer, Tracy R. A1 - Milaneschi, Yuri A1 - Mirza-Schreiber, Nazanin A1 - Moreira, Jose C. V. A1 - Mühleisen, Thomas W. A1 - Müller-Myhsok, Bertram A1 - Najt, Pablo A1 - Nakahara, Soichiro A1 - Nho, Kwangsik A1 - Olde Loohuis, Loes M. A1 - Orfanos, Dimitri Papadopoulos A1 - Pearson, John F. A1 - Pitcher, Toni L. A1 - Pütz, Benno A1 - Quidé, Yann A1 - Ragothaman, Anjanibhargavi A1 - Rashid, Faisal M. A1 - Reay, William R. A1 - Redlich, Ronny A1 - Reinbold, Céline S. A1 - Repple, Jonathan A1 - Richard, Geneviève A1 - Riedel, Brandalyn C. A1 - Risacher, Shannon L. A1 - Rocha, Cristiane S. A1 - Mota, Nina Roth A1 - Salminen, Lauren A1 - Saremi, Arvin A1 - Saykin, Andrew J. A1 - Schlag, Fenja A1 - Schmaal, Lianne A1 - Schofield, Peter R. A1 - Secolin, Rodrigo A1 - Shapland, Chin Yang A1 - Shen, Li A1 - Shin, Jean A1 - Shumskaya, Elena A1 - Sønderby, Ida E. A1 - Sprooten, Emma A1 - Tansey, Katherine E. A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Tordesillas-Gutierrez, Diana A1 - Turner, Jessica A. A1 - Uhlmann, Anne A1 - Vallerga, Costanza Ludovica A1 - van der Meer, Dennis A1 - van Donkelaar, Marjolein M. J. A1 - van Eijk, Liza A1 - van Erp, Theo G. M. A1 - van Haren, Neeltje E. M. A1 - van Rooij, Daan A1 - van Tol, Marie-Jose A1 - Veldink, Jan H. A1 - Verhoef, Ellen A1 - Walton, Esther A1 - Wang, Mingyuan A1 - Wang, Yunpeng A1 - Wardlaw, Joanna M. A1 - Wen, Wei A1 - Westlye, Lars T. A1 - Whelan, Christopher D. A1 - Witt, Stephanie H. A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wolfers, Thomas A1 - Wu, Jing Qin A1 - Yasuda, Clarissa L. A1 - Zaremba, Dario A1 - Zhang, Zuo A1 - Zwiers, Marcel P. A1 - Artiges, Eric A1 - Assareh, Amelia A. A1 - Ayesa-Arriola, Rosa A1 - Belger, Aysenil A1 - Brandt, Christine L. A1 - Brown, Gregory G. A1 - Cichon, Sven A1 - Curran, Joanne E. A1 - Davies, Gareth E. A1 - Degenhardt, Franziska A1 - Dennis, Michelle F. A1 - Dietsche, Bruno A1 - Djurovic, Srdjan A1 - Doherty, Colin P. A1 - Espiritu, Ryan A1 - Garijo, Daniel A1 - Gil, Yolanda A1 - Gowland, Penny A. A1 - Green, Robert C. A1 - Häusler, Alexander N. A1 - Heindel, Walter A1 - Ho, Beng-Choon A1 - Hoffmann, Wolfgang U. A1 - Holsboer, Florian A1 - Homuth, Georg A1 - Hosten, Norbert A1 - Jack, Clifford R. A1 - Jang, MiHyun A1 - Jansen, Andreas A1 - Kimbrel, Nathan A. A1 - Kolskår, Knut A1 - Koops, Sanne A1 - Krug, Axel A1 - Lim, Kelvin O. A1 - Luykx, Jurjen J. A1 - Mathalon, Daniel H. A1 - Mather, Karen A. A1 - Mattay, Venkata S. A1 - Matthews, Sarah A1 - Mayoral Van Son, Jaqueline A1 - McEwen, Sarah C. A1 - Melle, Ingrid A1 - Morris, Derek W. A1 - Mueller, Bryon A. A1 - Nauck, Matthias A1 - Nordvik, Jan E. A1 - Nöthen, Markus M. A1 - O’Leary, Daniel S. A1 - Opel, Nils A1 - Martinot, Marie-Laure Paillère A1 - Pike, G. Bruce A1 - Preda, Adrian A1 - Quinlan, Erin B. A1 - Rasser, Paul E. A1 - Ratnakar, Varun A1 - Reppermund, Simone A1 - Steen, Vidar M. A1 - Tooney, Paul A. A1 - Torres, Fábio R. A1 - Veltman, Dick J. A1 - Voyvodic, James T. A1 - Whelan, Robert A1 - White, Tonya A1 - Yamamori, Hidenaga A1 - Adams, Hieab H. H. A1 - Bis, Joshua C. A1 - Debette, Stephanie A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Hofer, Edith A1 - Ikram, M. Arfan A1 - Launer, Lenore A1 - Longstreth, W. T. A1 - Lopez, Oscar L. A1 - Mazoyer, Bernard A1 - Mosley, Thomas H. A1 - Roshchupkin, Gennady V. A1 - Satizabal, Claudia L. A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Yang, Qiong A1 - Alvim, Marina K. M. A1 - Ames, David A1 - Anderson, Tim J. A1 - Andreassen, Ole A. A1 - Arias-Vasquez, Alejandro A1 - Bastin, Mark E. A1 - Baune, Bernhard T. A1 - Beckham, Jean C. A1 - Blangero, John A1 - Boomsma, Dorret I. A1 - Brodaty, Henry A1 - Brunner, Han G. A1 - Buckner, Randy L. A1 - Buitelaar, Jan K. A1 - Bustillo, Juan R. A1 - Cahn, Wiepke A1 - Cairns, Murray J. A1 - Calhoun, Vince A1 - Carr, Vaughan J. A1 - Caseras, Xavier A1 - Caspers, Svenja A1 - Cavalleri, Gianpiero L. A1 - Cendes, Fernando A1 - Corvin, Aiden A1 - Crespo-Facorro, Benedicto A1 - Dalrymple-Alford, John C. A1 - Dannlowski, Udo A1 - de Geus, Eco J. C. A1 - Deary, Ian J. A1 - Delanty, Norman A1 - Depondt, Chantal A1 - Desrivières, Sylvane A1 - Donohoe, Gary A1 - Espeseth, Thomas A1 - Fernández, Guillén A1 - Fisher, Simon E. A1 - Flor, Herta A1 - Forstner, Andreas J. A1 - Francks, Clyde A1 - Franke, Barbara A1 - Glahn, David C. A1 - Gollub, Randy L. A1 - Grabe, Hans J. A1 - Gruber, Oliver A1 - Håberg, Asta K. A1 - Hariri, Ahmad R. A1 - Hartman, Catharina A. A1 - Hashimoto, Ryota A1 - Heinz, Andreas A1 - Henskens, Frans A. A1 - Hillegers, Manon H. J. A1 - Hoekstra, Pieter J. A1 - Holmes, Avram J. A1 - Hong, L. Elliot A1 - Hopkins, William D. A1 - Hulshoff Pol, Hilleke E. A1 - Jernigan, Terry L. A1 - Jönsson, Erik G. A1 - Kahn, René S. A1 - Kennedy, Martin A. A1 - Kircher, Tilo T. J. A1 - Kochunov, Peter A1 - Kwok, John B. J. A1 - Le Hellard, Stephanie A1 - Loughland, Carmel M. A1 - Martin, Nicholas G. A1 - Martinot, Jean-Luc A1 - McDonald, Colm A1 - McMahon, Katie L. A1 - Meyer-Lindenberg, Andreas A1 - Michie, Patricia T. A1 - Morey, Rajendra A. A1 - Mowry, Bryan A1 - Nyberg, Lars A1 - Oosterlaan, Jaap A1 - Ophoff, Roel A. A1 - Pantelis, Christos A1 - Paus, Tomáš A1 - Pausova, Zdenka A1 - Penninx, Brenda W. J. H. A1 - Polderman, Tinca J. C. A1 - Posthuma, Danielle A1 - Rietschel, Marcella A1 - Roffman, Joshua L. A1 - Rowland, Laura M. A1 - Sachdev, Perminder S. A1 - Sämann, Philipp G. A1 - Schall, Ulrich A1 - Schumann, Gunter A1 - Scott, Rodney J. A1 - Sim, Kang A1 - Sisodiya, Sanjay M. A1 - Smoller, Jordan W. A1 - Sommer, Iris E. A1 - St Pourcain, Beate A1 - Stein, Dan J. A1 - Toga, Arthur W. A1 - Trollor, Julian N. A1 - Van der Wee, Nic J. A. A1 - van ’t Ent, Dennis A1 - Völzke, Henry A1 - Walter, Henrik A1 - Weber, Bernd A1 - Weinberger, Daniel R. A1 - Wright, Margaret J. A1 - Zhou, Juan A1 - Stein, Jason L. A1 - Thompson, Paul M. A1 - Medland, Sarah E. VL - 367 UR - https://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.aay6690 IS - 6484 JO - Science ER - TY - JOUR T1 - {Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults JF - Nat Commun Y1 - 2020 A1 - Hofer, E. A1 - Roshchupkin, G. V. A1 - Adams, H. H. H. A1 - Knol, M. J. A1 - Lin, H. A1 - Li, S. A1 - Zare, H. A1 - Ahmad, S. A1 - Armstrong, N. J. A1 - Satizabal, C. L. A1 - Bernard, M. A1 - Bis, J. C. A1 - Gillespie, N. A. A1 - Luciano, M. A1 - Mishra, A. A1 - Scholz, M. A1 - Teumer, A. A1 - Xia, R. A1 - Jian, X. A1 - Mosley, T. H. A1 - Saba, Y. A1 - Pirpamer, L. A1 - Seiler, S. A1 - Becker, J. T. A1 - Carmichael, O. A1 - Rotter, J. I. A1 - Psaty, B. M. A1 - Lopez, O. L. A1 - Amin, N. A1 - van der Lee, S. J. A1 - Yang, Q. A1 - Himali, J. J. A1 - Maillard, P. A1 - Beiser, A. S. A1 - DeCarli, C. A1 - Karama, S. A1 - Lewis, L. A1 - Harris, M. A1 - Bastin, M. E. A1 - Deary, I. J. A1 - Veronica Witte, A. A1 - Beyer, F. A1 - Loeffler, M. A1 - Mather, K. A. A1 - Schofield, P. R. A1 - Thalamuthu, A. A1 - Kwok, J. B. A1 - Wright, M. J. A1 - Ames, D. A1 - Trollor, J. A1 - Jiang, J. A1 - Brodaty, H. A1 - Wen, W. A1 - Vernooij, M. W. A1 - Hofman, A. A1 - Uitterlinden, A. G. A1 - Niessen, W. J. A1 - Wittfeld, K. A1 - B?low, R. A1 - V?lker, U. A1 - Pausova, Z. A1 - Bruce Pike, G. A1 - Maingault, S. A1 - Crivello, F. A1 - Tzourio, C. A1 - Amouyel, P. A1 - Mazoyer, B. A1 - Neale, M. C. A1 - Franz, C. E. A1 - Lyons, M. J. A1 - Panizzon, M. S. A1 - Andreassen, O. A. A1 - Dale, A. M. A1 - Logue, M. A1 - Grasby, K. L. A1 - Jahanshad, N. A1 - Painter, J. N. A1 - Colodro-Conde, L. A1 - Bralten, J. A1 - Hibar, D. P. A1 - Lind, P. A. A1 - Pizzagalli, F. A1 - Stein, J. L. A1 - Thompson, P. M. A1 - Medland, S. E. A1 - Sachdev, P. S. A1 - Kremen, W. S. A1 - Wardlaw, J. M. A1 - Villringer, A. A1 - van Duijn, C. M. A1 - Grabe, H. J. A1 - Longstreth, W. T. A1 - Fornage, M. A1 - Paus, T. A1 - Debette, S. A1 - Arfan Ikram, M. A1 - Schmidt, H. A1 - Schmidt, R. A1 - Seshadri, S. A1 - Grasby, K. L. A1 - Jahanshad, N. A1 - Painter, J. N. A1 - Colodro-Conde, L. A1 - Bralten, J. A1 - Hibar, D. P. A1 - Lind, P. A. A1 - Pizzagalli, F. A1 - Ching, C. R. K. A1 - McMahon, M. A. B. A1 - Shatokhina, N. A1 - Zsembik, L. C. P. A1 - Agartz, I. A1 - Alhusaini, S. A1 - Almeida, M. A. A. A1 - Aln?s, D. A1 - Amlien, I. K. A1 - Andersson, M. A1 - Ard, T. A1 - Armstrong, N. J. A1 - Ashley-Koch, A. A1 - Bernard, M. A1 - Brouwer, R. M. A1 - Buimer, E. E. L. A1 - B?low, R. A1 - B?rger, C. A1 - Cannon, D. M. A1 - Chakravarty, M. A1 - Chen, Q. A1 - Cheung, J. W. A1 - Couvy-Duchesne, B. A1 - Dale, A. M. A1 - Dalvie, S. A1 - de Araujo, T. K. A1 - de Zubicaray, G. I. A1 - de Zwarte, S. M. C. A1 - den Braber, A. A1 - Doan, N. T. A1 - Dohm, K. A1 - Ehrlich, S. A1 - Engelbrecht, H. R. 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A1 - Moreira, J. C. V. A1 - M?hleisen, T. W. A1 - M?ller-Myhsok, B. A1 - Najt, P. A1 - Nakahara, S. A1 - Nho, K. A1 - Olde Loohuis, L. M. A1 - Orfanos, D. P. A1 - Pearson, J. F. A1 - Pitcher, T. L. A1 - P?tz, B. A1 - Ragothaman, A. A1 - Rashid, F. M. A1 - Redlich, R. A1 - Reinbold, C. S. A1 - Repple, J. A1 - Richard, G. A1 - Riedel, B. C. A1 - Risacher, S. L. A1 - Rocha, C. S. A1 - Mota, N. R. A1 - Salminen, L. A1 - Saremi, A. A1 - Saykin, A. J. A1 - Schlag, F. A1 - Schmaal, L. A1 - Schofield, P. R. A1 - Secolin, R. A1 - Shapland, C. Y. A1 - Shen, L. A1 - Shin, J. A1 - Shumskaya, E. A1 - S?nderby, I. E. A1 - Sprooten, E. A1 - Strike, L. T. A1 - Tansey, K. E. A1 - Teumer, A. A1 - Thalamuthu, A. A1 - Thomopoulos, S. I. A1 - Tordesillas-Guti?rrez, D. A1 - Turner, J. A. A1 - Uhlmann, A. A1 - Vallerga, C. L. A1 - van der Meer, D. A1 - van Donkelaar, M. M. J. A1 - van Eijk, L. A1 - van Erp, T. G. M. A1 - van Haren, N. E. M. A1 - van Rooij, D. A1 - van Tol, M. J. A1 - Veldink, J. H. A1 - Verhoef, E. A1 - Walton, E. A1 - Wang, M. A1 - Wang, Y. A1 - Wardlaw, J. M. A1 - Wen, W. A1 - Westlye, L. T. A1 - Whelan, C. D. A1 - Witt, S. H. A1 - Wittfeld, K. A1 - Wolf, C. A1 - Wolfers, T. A1 - Yasuda, C. L. A1 - Zaremba, D. A1 - Zhang, Z. A1 - Zhu, A. H. A1 - Zwiers, M. P. A1 - Artiges, E. A1 - Assareh, A. A. A1 - Ayesa-Arriola, R. A1 - Belger, A. A1 - Brandt, C. L. A1 - Brown, G. G. A1 - Cichon, S. A1 - Curran, J. E. A1 - Davies, G. E. A1 - Degenhardt, F. A1 - Dietsche, B. A1 - Djurovic, S. A1 - Doherty, C. P. A1 - Espiritu, R. A1 - Garijo, D. A1 - Gil, Y. A1 - Gowland, P. A. A1 - Green, R. C. A1 - H?usler, A. N. A1 - Heindel, W. A1 - Ho, B. C. A1 - Hoffmann, W. U. A1 - Holsboer, F. A1 - Homuth, G. A1 - Hosten, N. A1 - Jack, C. R. A1 - Jang, M. A1 - Jansen, A. A1 - Kolsk?r, K. A1 - Koops, S. A1 - Krug, A. A1 - Lim, K. O. A1 - Luykx, J. J. A1 - Mathalon, D. H. A1 - Mather, K. A. A1 - Mattay, V. S. A1 - Matthews, S. A1 - Son, J. M. V. A1 - McEwen, S. C. A1 - Melle, I. A1 - Morris, D. W. A1 - Mueller, B. A. A1 - Nauck, M. A1 - Nordvik, J. E. A1 - N?then, M. M. A1 - O'Leary, D. S. A1 - Opel, N. A1 - Martinot, M. -P. A1 - Pike, G. B. A1 - Preda, A. A1 - Quinlan, E. B. A1 - Ratnakar, V. A1 - Reppermund, S. A1 - Steen, V. M. A1 - Torres, F. R. A1 - Veltman, D. J. A1 - Voyvodic, J. T. A1 - Whelan, R. A1 - White, T. A1 - Yamamori, H. A1 - Alvim, M. K. M. A1 - Ames, D. A1 - Anderson, T. J. A1 - Andreassen, O. A. A1 - Arias-Vasquez, A. A1 - Bastin, M. E. A1 - Baune, B. T. A1 - Blangero, J. A1 - Boomsma, D. I. A1 - Brodaty, H. A1 - Brunner, H. G. A1 - Buckner, R. L. A1 - Buitelaar, J. K. A1 - Bustillo, J. R. A1 - Cahn, W. A1 - Calhoun, V. A1 - Caseras, X. A1 - Caspers, S. A1 - Cavalleri, G. L. A1 - Cendes, F. A1 - Corvin, A. A1 - Crespo-Facorro, B. A1 - Dalrymple-Alford, J. C. A1 - Dannlowski, U. A1 - de Geus, E. J. C. A1 - Deary, I. J. A1 - Delanty, N. A1 - Depondt, C. A1 - Desrivi?res, S. A1 - Donohoe, G. A1 - Espeseth, T. A1 - Fern?ndez, G. A1 - Fisher, S. E. A1 - Flor, H. A1 - Forstner, A. J. A1 - Francks, C. A1 - Franke, B. A1 - Glahn, D. C. A1 - Gollub, R. L. A1 - Grabe, H. J. A1 - Gruber, O. A1 - H?berg, A. K. A1 - Hariri, A. R. A1 - Hartman, C. A. A1 - Hashimoto, R. A1 - Heinz, A. A1 - Hillegers, M. H. J. A1 - Hoekstra, P. J. A1 - Holmes, A. J. A1 - Hong, L. E. A1 - Hopkins, W. D. A1 - Hulshoff Pol, H. E. A1 - Jernigan, T. L. A1 - J?nsson, E. G. A1 - Kahn, R. S. A1 - Kennedy, M. A. A1 - Kircher, T. T. J. A1 - Kochunov, P. A1 - Kwok, J. B. J. A1 - Hellard, S. L. A1 - Martin, N. G. A1 - Martinot, J. - A1 - McDonald, C. A1 - McMahon, K. L. A1 - Meyer-Lindenberg, A. A1 - Morey, R. A. A1 - Nyberg, L. A1 - Oosterlaan, J. A1 - Ophoff, R. A. A1 - Paus, T. A1 - Pausova, Z. A1 - Penninx, B. W. J. H. A1 - Polderman, T. J. C. A1 - Posthuma, D. A1 - Rietschel, M. A1 - Roffman, J. L. A1 - Rowland, L. M. A1 - Sachdev, P. S. A1 - S?mann, P. G. A1 - Schumann, G. A1 - Sim, K. A1 - Sisodiya, S. M. A1 - Smoller, J. W. A1 - Sommer, I. E. A1 - Pourcain, B. S. A1 - Stein, D. J. A1 - Toga, A. W. A1 - Trollor, J. N. A1 - Van der Wee, N. J. A. A1 - van 't Ent, D. A1 - V?lzke, H. A1 - Walter, H. A1 - Weber, B. A1 - Weinberger, D. R. A1 - Wright, M. J. A1 - Zhou, J. A1 - Stein, J. L. A1 - Thompson, P. M. A1 - Medland, S. E. AB - Cortical 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. VL - 11 ER - TY - JOUR T1 - {Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation JF - Circ Genom Precis Med Y1 - 2020 A1 - Weng, L. C. A1 - Hall, A. W. A1 - Choi, S. H. A1 - Jurgens, S. J. A1 - Haessler, J. A1 - Bihlmeyer, N. A. A1 - Grarup, N. A1 - Lin, H. A1 - Teumer, A. A1 - Li-Gao, R. A1 - Yao, J. A1 - Guo, X. A1 - Brody, J. A. A1 - M?ller-Nurasyid, M. A1 - Schramm, K. A1 - Verweij, N. A1 - van den Berg, M. E. A1 - van Setten, J. A1 - Isaacs, A. A1 - Ram?rez, J. A1 - Warren, H. R. A1 - Padmanabhan, S. A1 - Kors, J. A. A1 - de Boer, R. A. A1 - van der Meer, P. A1 - Sinner, M. F. A1 - Waldenberger, M. A1 - Psaty, B. M. A1 - Taylor, K. D. A1 - V?lker, U. A1 - Kanters, J. K. A1 - Li, M. A1 - Alonso, A. A1 - Perez, M. V. A1 - Vaartjes, I. A1 - Bots, M. L. A1 - Huang, P. L. A1 - Heckbert, S. R. A1 - Lin, H. J. A1 - Kornej, J. A1 - Munroe, P. B. A1 - van Duijn, C. M. A1 - Asselbergs, F. W. A1 - Stricker, B. H. A1 - van der Harst, P. A1 - K??b, S. A1 - Peters, A. A1 - Sotoodehnia, N. A1 - Rotter, J. I. A1 - Mook-Kanamori, D. O. A1 - D?rr, M. A1 - Felix, S. B. A1 - Linneberg, A. A1 - Hansen, T. A1 - Arking, D. E. A1 - Kooperberg, C. A1 - Benjamin, E. J. A1 - Lunetta, K. L. A1 - Ellinor, P. T. A1 - Lubitz, S. A. AB - Background - 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. ER - TY - JOUR T1 - Genetic 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. JF - PLoS One Y1 - 2020 A1 - Hahn, Julie A1 - Fu, Yi-Ping A1 - Brown, Michael R A1 - Bis, Joshua C A1 - de Vries, Paul S A1 - Feitosa, Mary F A1 - Yanek, Lisa R A1 - Weiss, Stefan A1 - Giulianini, Franco A1 - Smith, Albert Vernon A1 - Guo, Xiuqing A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Chen, Yii-Der Ida A1 - Franco, Oscar H A1 - Grove, Megan A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Hwang, Shih-Jen A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Markus, Marcello R P A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Yao, Jie A1 - Chasman, Daniel I A1 - Dörr, Marcus A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Post, Wendy A1 - Psaty, Bruce M A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Morrison, Alanna C KW - Aging KW - Coronary Artery Disease KW - Cross-Sectional Studies KW - Europe KW - European Continental Ancestry Group KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: 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.

VL - 15 IS - 11 ER - TY - JOUR T1 - Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. JF - Diabetes Y1 - 2020 A1 - Yaghootkar, Hanieh A1 - Zhang, Yiying A1 - Spracklen, Cassandra N A1 - Karaderi, Tugce A1 - Huang, Lam Opal A1 - Bradfield, Jonathan A1 - Schurmann, Claudia A1 - Fine, Rebecca S A1 - Preuss, Michael H A1 - Kutalik, Zoltán A1 - Wittemans, Laura Bl A1 - Lu, Yingchang A1 - Metz, Sophia A1 - Willems, Sara M A1 - Li-Gao, Ruifang A1 - Grarup, Niels A1 - Wang, Shuai A1 - Molnos, Sophie A1 - Sandoval-Zárate, América A A1 - Nalls, Mike A A1 - Lange, Leslie A A1 - Haesser, Jeffrey A1 - Guo, Xiuqing A1 - Lyytikäinen, Leo-Pekka A1 - Feitosa, Mary F A1 - Sitlani, Colleen M A1 - Venturini, Cristina A1 - Mahajan, Anubha A1 - Kacprowski, Tim A1 - Wang, Carol A A1 - Chasman, Daniel I A1 - Amin, Najaf A1 - Broer, Linda A1 - Robertson, Neil A1 - Young, Kristin L A1 - Allison, Matthew A1 - Auer, Paul L A1 - Blüher, Matthias A1 - Borja, Judith B A1 - Bork-Jensen, Jette A1 - Carrasquilla, Germán D A1 - Christofidou, Paraskevi A1 - Demirkan, Ayse A1 - Doege, Claudia A A1 - Garcia, Melissa E A1 - Graff, Mariaelisa A1 - Guo, Kaiying A1 - Hakonarson, Hakon A1 - Hong, Jaeyoung A1 - Ida Chen, Yii-Der A1 - Jackson, Rebecca A1 - Jakupović, Hermina A1 - Jousilahti, Pekka A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Kizer, Jorge R A1 - Kriebel, Jennifer A1 - LeDuc, Charles A A1 - Li, Jin A1 - Lind, Lars A1 - Luan, Jian'an A1 - Mackey, David A1 - Mangino, Massimo A1 - Männistö, Satu A1 - Martin Carli, Jayne F A1 - Medina-Gómez, Carolina A1 - Mook-Kanamori, Dennis O A1 - Morris, Andrew P A1 - de Mutsert, Renée A1 - Nauck, Matthias A1 - Nedeljkovic, Ivana A1 - Pennell, Craig E A1 - Pradhan, Arund D A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Scott, Robert A A1 - Skaaby, Tea A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Wu, Ying A1 - Yao, Jie A1 - Walker, Mark A1 - North, Kari E A1 - Kovacs, Peter A1 - Ikram, M Arfan A1 - van Duijn, Cornelia M A1 - Ridker, Paul M A1 - Lye, Stephen A1 - Homuth, Georg A1 - Ingelsson, Erik A1 - Spector, Tim D A1 - McKnight, Barbara A1 - Province, Michael A A1 - Lehtimäki, Terho A1 - Adair, Linda S A1 - Rotter, Jerome I A1 - Reiner, Alexander P A1 - Wilson, James G A1 - Harris, Tamara B A1 - Ripatti, Samuli A1 - Grallert, Harald A1 - Meigs, James B A1 - Salomaa, Veikko A1 - Hansen, Torben A1 - Willems van Dijk, Ko A1 - Wareham, Nicholas J A1 - Grant, Struan Fa A1 - Langenberg, Claudia A1 - Frayling, Timothy M A1 - Lindgren, Cecilia M A1 - Mohlke, Karen L A1 - Leibel, Rudolph L A1 - Loos, Ruth Jf A1 - Kilpeläinen, Tuomas O AB -

Leptin 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.

ER - TY - JOUR T1 - {Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure JF - Nat Commun Y1 - 2020 A1 - Shah, S. A1 - Henry, A. A1 - Roselli, C. A1 - Lin, H. A1 - Sveinbj?rnsson, G. A1 - Fatemifar, G. A1 - Hedman, ?. K. A1 - Wilk, J. B. A1 - Morley, M. P. A1 - Chaffin, M. D. A1 - Helgadottir, A. A1 - Verweij, N. A1 - Dehghan, A. A1 - Almgren, P. A1 - Andersson, C. A1 - Aragam, K. G. A1 - ?rnl?v, J. A1 - Backman, J. D. A1 - Biggs, M. L. A1 - Bloom, H. L. A1 - Brandimarto, J. A1 - Brown, M. R. A1 - Buckbinder, L. A1 - Carey, D. J. A1 - Chasman, D. I. A1 - Chen, X. A1 - Chen, X. A1 - Chung, J. A1 - Chutkow, W. A1 - Cook, J. P. A1 - Delgado, G. E. A1 - Denaxas, S. A1 - Doney, A. S. A1 - D?rr, M. A1 - Dudley, S. C. A1 - Dunn, M. E. A1 - Engstr?m, G. A1 - Esko, T. A1 - Felix, S. B. A1 - Finan, C. A1 - Ford, I. A1 - Ghanbari, M. A1 - Ghasemi, S. A1 - Giedraitis, V. A1 - Giulianini, F. A1 - Gottdiener, J. S. A1 - Gross, S. A1 - Gu?bjartsson, D. F. A1 - Gutmann, R. A1 - Haggerty, C. M. A1 - van der Harst, P. A1 - Hyde, C. L. A1 - Ingelsson, E. A1 - Jukema, J. W. A1 - Kavousi, M. A1 - Khaw, K. T. A1 - Kleber, M. E. A1 - K?ber, L. A1 - Koekemoer, A. A1 - Langenberg, C. A1 - Lind, L. A1 - Lindgren, C. M. A1 - London, B. A1 - Lotta, L. A. A1 - Lovering, R. C. A1 - Luan, J. A1 - Magnusson, P. A1 - Mahajan, A. A1 - Margulies, K. B. A1 - M?rz, W. A1 - Melander, O. A1 - Mordi, I. R. A1 - Morgan, T. A1 - Morris, A. D. A1 - Morris, A. P. A1 - Morrison, A. C. A1 - Nagle, M. W. A1 - Nelson, C. P. A1 - Niessner, A. A1 - Niiranen, T. A1 - O'Donoghue, M. L. A1 - Owens, A. T. A1 - Palmer, C. N. A. A1 - Parry, H. M. A1 - Perola, M. A1 - Portilla-Fernandez, E. A1 - Psaty, B. M. A1 - Rice, K. M. A1 - Ridker, P. M. A1 - Romaine, S. P. R. A1 - Rotter, J. I. A1 - Salo, P. A1 - Salomaa, V. A1 - van Setten, J. A1 - Shalaby, A. A. A1 - Smelser, D. T. A1 - Smith, N. L. A1 - Stender, S. A1 - Stott, D. J. A1 - Svensson, P. A1 - Tammesoo, M. L. A1 - Taylor, K. D. A1 - Teder-Laving, M. A1 - Teumer, A. A1 - Thorgeirsson, G. A1 - Thorsteinsdottir, U. A1 - Torp-Pedersen, C. A1 - Trompet, S. A1 - Tyl, B. A1 - Uitterlinden, A. G. A1 - Veluchamy, A. A1 - V?lker, U. A1 - Voors, A. A. A1 - Wang, X. A1 - Wareham, N. J. A1 - Waterworth, D. A1 - Weeke, P. E. A1 - Weiss, R. A1 - Wiggins, K. L. A1 - Xing, H. A1 - Yerges-Armstrong, L. M. A1 - Yu, B. A1 - Zannad, F. A1 - Zhao, J. H. A1 - Hemingway, H. A1 - Samani, N. J. A1 - McMurray, J. J. V. A1 - Yang, J. A1 - Visscher, P. M. A1 - Newton-Cheh, C. A1 - Malarstig, A. A1 - Holm, H. A1 - Lubitz, S. A. A1 - Sattar, N. A1 - Holmes, M. V. A1 - Cappola, T. P. A1 - Asselbergs, F. W. A1 - Hingorani, A. D. A1 - Kuchenbaecker, K. A1 - Ellinor, P. T. A1 - Lang, C. C. A1 - Stefansson, K. A1 - Smith, J. G. A1 - Vasan, R. S. A1 - Swerdlow, D. I. A1 - Lumbers, R. T. A1 - Abecasis, G. A1 - Backman, J. A1 - Bai, X. A1 - Balasubramanian, S. A1 - Banerjee, N. A1 - Baras, A. A1 - Barnard, L. A1 - Beechert, C. A1 - Blumenfeld, A. A1 - Cantor, M. A1 - Chai, Y. A1 - Chung, J. A1 - Coppola, G. A1 - Damask, A. A1 - Dewey, F. A1 - Economides, A. A1 - Eom, G. A1 - Forsythe, C. A1 - Fuller, E. D. A1 - Gu, Z. A1 - Gurski, L. A1 - Guzzardo, P. M. A1 - Habegger, L. A1 - Hahn, Y. A1 - Hawes, A. A1 - van Hout, C. A1 - Jones, M. B. A1 - Khalid, S. A1 - Lattari, M. A1 - Li, A. A1 - Lin, N. A1 - Liu, D. A1 - Lopez, A. A1 - Manoochehri, K. A1 - Marchini, J. A1 - Marcketta, A. A1 - Maxwell, E. K. A1 - McCarthy, S. A1 - Mitnaul, L. J. A1 - O'Dushlaine, C. A1 - Overton, J. D. A1 - Padilla, M. S. A1 - Paulding, C. A1 - Penn, J. A1 - Pradhan, M. A1 - Reid, J. G. A1 - Schleicher, T. D. A1 - Schurmann, C. A1 - Shuldiner, A. A1 - Staples, J. C. A1 - Sun, D. A1 - Toledo, K. A1 - Ulloa, R. H. A1 - Widom, L. A1 - Wolf, S. E. A1 - Yadav, A. A1 - Ye, B. AB - Heart 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. VL - 11 ER - TY - JOUR T1 - {Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke JF - Stroke Y1 - 2020 A1 - Keene, K. L. A1 - Hyacinth, H. I. A1 - Bis, J. C. A1 - Kittner, S. J. A1 - Mitchell, B. D. A1 - Cheng, Y. C. A1 - Pare, G. A1 - Chong, M. A1 - O'Donnell, M. A1 - Meschia, J. F. A1 - Chen, W. M. A1 - Sale, M. M. A1 - Rich, S. S. A1 - Nalls, M. A. A1 - Zonderman, A. B. A1 - Evans, M. K. A1 - Wilson, J. G. A1 - Correa, A. A1 - Markus, H. S. A1 - Traylor, M. A1 - Lewis, C. M. A1 - Carty, C. L. A1 - Reiner, A. A1 - Haessler, J. A1 - Langefeld, C. D. A1 - Gottesman, R. A1 - Mosley, T. H. A1 - Woo, D. A1 - Yaffe, K. A1 - Liu, Y. A1 - Longstreth, W. T. A1 - Psaty, B. M. A1 - Kooperberg, C. A1 - Lange, L. A. A1 - Sacco, R. A1 - Rundek, T. A1 - Lee, J. M. A1 - Cruchaga, C. A1 - Furie, K. L. A1 - Arnett, D. K. A1 - Benavente, O. R. A1 - Grewal, R. P. A1 - Peddareddygari, L. R. A1 - Dichgans, M. A1 - Malik, R. A1 - Worrall, B. B. A1 - Fornage, M. AB - Stroke 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. VL - 51 ER - TY - JOUR T1 - Incorporating sampling weights into robust estimation of Cox proportional hazards regression model, with illustration in the Multi-Ethnic Study of Atherosclerosis. JF - BMC Med Res Methodol Y1 - 2020 A1 - Sitlani, Colleen M A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Rice, Kenneth M A1 - Olson, Nels C A1 - Doyle, Margaret F A1 - Huber, Sally A A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - C Delaney, Joseph A AB -

BACKGROUND: 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.

VL - 20 IS - 1 ER - TY - JOUR T1 - {An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms JF - Sci Rep Y1 - 2020 A1 - Wildisen, L. A1 - Del Giovane, C. A1 - Moutzouri, E. A1 - Beglinger, S. A1 - Syrogiannouli, L. A1 - Collet, T. H. A1 - Cappola, A. R. A1 - ?svold, B. O. A1 - Bakker, S. J. L. A1 - Yeap, B. B. A1 - Almeida, O. P. A1 - Ceresini, G. A1 - Dullaart, R. P. F. A1 - Ferrucci, L. A1 - Grabe, H. A1 - Jukema, J. W. A1 - Nauck, M. A1 - Trompet, S. A1 - V?lzke, H. A1 - Westendorp, R. A1 - Gussekloo, J. A1 - Kl?ppel, S. A1 - Aujesky, D. A1 - Bauer, D. A1 - Peeters, R. A1 - Feller, M. A1 - Rodondi, N. AB - {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 0.76 VL - 10 ER - TY - JOUR T1 - Inherited causes of clonal haematopoiesis in 97,691 whole genomes. JF - Nature Y1 - 2020 A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Nandakumar, Satish K A1 - Fulco, Charles P A1 - Bao, Erik L A1 - Zekavat, Seyedeh M A1 - Szeto, Mindy D A1 - Liao, Xiaotian A1 - Leventhal, Matthew J A1 - Nasser, Joseph A1 - Chang, Kyle A1 - Laurie, Cecelia A1 - Burugula, Bala Bharathi A1 - Gibson, Christopher J A1 - Lin, Amy E A1 - Taub, Margaret A A1 - Aguet, Francois A1 - Ardlie, Kristin A1 - Mitchell, Braxton D A1 - Barnes, Kathleen C A1 - Moscati, Arden A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Silverman, Edwin K A1 - Weiss, Scott T A1 - Palmer, Nicholette D A1 - Vasan, Ramachandran S A1 - Burchard, Esteban G A1 - Kardia, Sharon L R A1 - He, Jiang A1 - Kaplan, Robert C A1 - Smith, Nicholas L A1 - Arnett, Donna K A1 - Schwartz, David A A1 - Correa, Adolfo A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Konkle, Barbara A A1 - Custer, Brian A1 - Peralta, Juan M A1 - Gui, Hongsheng A1 - Meyers, Deborah A A1 - McGarvey, Stephen T A1 - Chen, Ida Yii-Der A1 - Shoemaker, M Benjamin A1 - Peyser, Patricia A A1 - Broome, Jai G A1 - Gogarten, Stephanie M A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Montasser, May E A1 - Daya, Michelle A1 - Kenny, Eimear E A1 - North, Kari E A1 - Launer, Lenore J A1 - Cade, Brian E A1 - Bis, Joshua C A1 - Cho, Michael H A1 - Lasky-Su, Jessica A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Mak, Angel C Y A1 - Becker, Lewis C A1 - Smith, Jennifer A A1 - Kelly, Tanika N A1 - Aslibekyan, Stella A1 - Heckbert, Susan R A1 - Tiwari, Hemant K A1 - Yang, Ivana V A1 - Heit, John A A1 - Lubitz, Steven A A1 - Johnsen, Jill M A1 - Curran, Joanne E A1 - Wenzel, Sally E A1 - Weeks, Daniel E A1 - Rao, Dabeeru C A1 - Darbar, Dawood A1 - Moon, Jee-Young A1 - Tracy, Russell P A1 - Buth, Erin J A1 - Rafaels, Nicholas A1 - Loos, Ruth J F A1 - Durda, Peter A1 - Liu, Yongmei A1 - Hou, Lifang A1 - Lee, Jiwon A1 - Kachroo, Priyadarshini A1 - Freedman, Barry I A1 - Levy, Daniel A1 - Bielak, Lawrence F A1 - Hixson, James E A1 - Floyd, James S A1 - Whitsel, Eric A A1 - Ellinor, Patrick T A1 - Irvin, Marguerite R A1 - Fingerlin, Tasha E A1 - Raffield, Laura M A1 - Armasu, Sebastian M A1 - Wheeler, Marsha M A1 - Sabino, Ester C A1 - Blangero, John A1 - Williams, L Keoki A1 - Levy, Bruce D A1 - Sheu, Wayne Huey-Herng A1 - Roden, Dan M A1 - Boerwinkle, Eric A1 - Manson, JoAnn E A1 - Mathias, Rasika A A1 - Desai, Pinkal A1 - Taylor, Kent D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Zhao, Hongyu A1 - Lange, Ethan A1 - Lange, Leslie A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Scheet, Paul A1 - Kitzman, Jacob O A1 - Lander, Eric S A1 - Engreitz, Jesse M A1 - Ebert, Benjamin L A1 - Reiner, Alexander P A1 - Jaiswal, Siddhartha A1 - Abecasis, Goncalo A1 - Sankaran, Vijay G A1 - Kathiresan, Sekar A1 - Natarajan, Pradeep AB -

Age 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.

VL - 586 IS - 7831 ER - TY - JOUR T1 - Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts. JF - Atherosclerosis Y1 - 2020 A1 - Olson, Nels C A1 - Sitlani, Colleen M A1 - Doyle, Margaret F A1 - Huber, Sally A A1 - Landay, Alan L A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Delaney, Joseph A AB -

BACKGROUND 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.

VL - 300 ER - TY - JOUR T1 - Level and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90. JF - J Gerontol A Biol Sci Med Sci Y1 - 2020 A1 - Häberle, Astrid D A1 - Biggs, Mary L A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Newman, Anne B A1 - Shlipak, Michael G A1 - Gottdiener, John A1 - Wu, Chenkai A1 - Gardin, Julius M A1 - Bansal, Nisha A1 - Odden, Michelle C AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. JF - Eur J Epidemiol Y1 - 2020 A1 - Zheng, Yan A1 - Huang, Tao A1 - Wang, Tiange A1 - Mei, Zhendong A1 - Sun, Zhonghan A1 - Zhang, Tao A1 - Ellervik, Christina A1 - Chai, Jin-Fang A1 - Sim, Xueling A1 - van Dam, Rob M A1 - Tai, E-Shyong A1 - Koh, Woon-Puay A1 - Dorajoo, Rajkumar A1 - Saw, Seang-Mei A1 - Sabanayagam, Charumathi A1 - Wong, Tien Yin A1 - Gupta, Preeti A1 - Rossing, Peter A1 - Ahluwalia, Tarunveer S A1 - Vinding, Rebecca K A1 - Bisgaard, Hans A1 - Bønnelykke, Klaus A1 - Wang, Yujie A1 - Graff, Mariaelisa A1 - Voortman, Trudy A1 - van Rooij, Frank J A A1 - Hofman, Albert A1 - van Heemst, Diana A1 - Noordam, Raymond A1 - Estampador, Angela C A1 - Varga, Tibor V A1 - Enzenbach, Cornelia A1 - Scholz, Markus A1 - Thiery, Joachim A1 - Burkhardt, Ralph A1 - Orho-Melander, Marju A1 - Schulz, Christina-Alexandra A1 - Ericson, Ulrika A1 - Sonestedt, Emily A1 - Kubo, Michiaki A1 - Akiyama, Masato A1 - Zhou, Ang A1 - Kilpeläinen, Tuomas O A1 - Hansen, Torben A1 - Kleber, Marcus E A1 - Delgado, Graciela A1 - McCarthy, Mark A1 - Lemaitre, Rozenn N A1 - Felix, Janine F A1 - Jaddoe, Vincent W V A1 - Wu, Ying A1 - Mohlke, Karen L A1 - Lehtimäki, Terho A1 - Wang, Carol A A1 - Pennell, Craig E A1 - Schunkert, Heribert A1 - Kessler, Thorsten A1 - Zeng, Lingyao A1 - Willenborg, Christina A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Grote, Veit A1 - Rzehak, Peter A1 - Koletzko, Berthold A1 - Erdmann, Jeanette A1 - Munz, Matthias A1 - Wu, Tangchun A1 - He, Meian A1 - Yu, Caizheng A1 - Lecoeur, Cécile A1 - Froguel, Philippe A1 - Corella, Dolores A1 - Moreno, Luis A A1 - Lai, Chao-Qiang A1 - Pitkänen, Niina A1 - Boreham, Colin A A1 - Ridker, Paul M A1 - Rosendaal, Frits R A1 - de Mutsert, Renée A1 - Power, Chris A1 - Paternoster, Lavinia A1 - Sørensen, Thorkild I A A1 - Tjønneland, Anne A1 - Overvad, Kim A1 - Djoussé, Luc A1 - Rivadeneira, Fernando A1 - Lee, Nanette R A1 - Raitakari, Olli T A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Langhendries, Jean-Paul A1 - Escribano, Joaquin A1 - Verduci, Elvira A1 - Dedoussis, George A1 - König, Inke A1 - Balkau, Beverley A1 - Coltell, Oscar A1 - Dallongeville, Jean A1 - Meirhaeghe, Aline A1 - Amouyel, Philippe A1 - Gottrand, Frédéric A1 - Pahkala, Katja A1 - Niinikoski, Harri A1 - Hyppönen, Elina A1 - März, Winfried A1 - Mackey, David A A1 - Gruszfeld, Dariusz A1 - Tucker, Katherine L A1 - Fumeron, Frédéric A1 - Estruch, Ramon A1 - Ordovas, Jose M A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - North, Kari E A1 - Chasman, Daniel I A1 - Qi, Lu AB -

Epidemiology 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.

VL - 35 IS - 7 ER - TY - JOUR T1 - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. JF - Kidney Int Y1 - 2020 A1 - Gorski, Mathias A1 - Jung, Bettina A1 - Li, Yong A1 - Matias-Garcia, Pamela R A1 - Wuttke, Matthias A1 - Coassin, Stefan A1 - Thio, Chris H L A1 - Kleber, Marcus E A1 - Winkler, Thomas W A1 - Wanner, Veronika A1 - Chai, Jin-Fang A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Feitosa, Mary F A1 - Ghasemi, Sahar A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Li, Man A1 - Nutile, Teresa A1 - Scholz, Markus A1 - Sieber, Karsten B A1 - Teumer, Alexander A1 - Tin, Adrienne A1 - Wang, Judy A1 - Tayo, Bamidele O A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Carroll, Robert J A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Coresh, Josef A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Gieger, Christian A1 - Hamet, Pavel A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Xian Foo, Valencia Hui A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Kähönen, Mika A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - O'Donoghue, Michelle L A1 - Orho-Melander, Marju A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Sabanayagam, Charumathi A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Strauch, Konstantin A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Tremblay, Johanne A1 - Chaker, Layal A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Yan A1 - Snieder, Harold A1 - Wanner, Christoph A1 - Böger, Carsten A A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Pattaro, Cristian A1 - Heid, Iris M AB -

Rapid 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.

ER - TY - JOUR T1 - {Mitochondrial DNA copy number and incident atrial fibrillation JF - BMC Med Y1 - 2020 A1 - Zhao, D. A1 - Bartz, T. M. A1 - Sotoodehnia, N. A1 - Post, W. S. A1 - Heckbert, S. R. A1 - Alonso, A. A1 - Longchamps, R. J. A1 - Castellani, C. A. A1 - Hong, Y. S. A1 - Rotter, J. I. A1 - Lin, H. J. A1 - O'Rourke, B. A1 - Pankratz, N. A1 - Lane, J. A. A1 - Yang, S. Y. A1 - Guallar, E. A1 - Arking, D. E. AB - Mechanistic 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. VL - 18 ER - TY - JOUR T1 - Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs. JF - Genome Med Y1 - 2020 A1 - Castellani, Christina A A1 - Longchamps, Ryan J A1 - Sumpter, Jason A A1 - Newcomb, Charles E A1 - Lane, John A A1 - Grove, Megan L A1 - Bressler, Jan A1 - Brody, Jennifer A A1 - Floyd, James S A1 - Bartz, Traci M A1 - Taylor, Kent D A1 - Wang, Penglong A1 - Tin, Adrienne A1 - Coresh, Josef A1 - Pankow, James S A1 - Fornage, Myriam A1 - Guallar, Eliseo A1 - O'Rourke, Brian A1 - Pankratz, Nathan A1 - Liu, Chunyu A1 - Levy, Daniel A1 - Sotoodehnia, Nona A1 - Boerwinkle, Eric A1 - Arking, Dan E AB -

BACKGROUND: 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JF - Nat Commun Y1 - 2020 A1 - Ntalla, Ioanna A1 - Weng, Lu-Chen A1 - Cartwright, James H A1 - Hall, Amelia Weber A1 - Sveinbjornsson, Gardar A1 - Tucker, Nathan R A1 - Choi, Seung Hoan A1 - Chaffin, Mark D A1 - Roselli, Carolina A1 - Barnes, Michael R A1 - Mifsud, Borbala A1 - Warren, Helen R A1 - Hayward, Caroline A1 - Marten, Jonathan A1 - Cranley, James J A1 - Concas, Maria Pina A1 - Gasparini, Paolo A1 - Boutin, Thibaud A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Araujo, Nathalia M A1 - Lima-Costa, Maria Fernanda A1 - Ribeiro, Antonio Luiz P A1 - Souza, Renan P A1 - Tarazona-Santos, Eduardo A1 - Giedraitis, Vilmantas A1 - Ingelsson, Erik A1 - Mahajan, Anubha A1 - Morris, Andrew P A1 - del Greco M, Fabiola A1 - Foco, Luisa A1 - Gögele, Martin A1 - Hicks, Andrew A A1 - Cook, James P A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Sundström, Johan A1 - Nelson, Christopher P A1 - Riaz, Muhammad B A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Ulivi, Sheila A1 - Kähönen, Mika A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Nikus, Kjell A1 - Caulfield, Mark J A1 - Dominiczak, Anna A1 - Padmanabhan, Sandosh A1 - Montasser, May E A1 - O'Connell, Jeff R A1 - Ryan, Kathleen A1 - Shuldiner, Alan R A1 - Aeschbacher, Stefanie A1 - Conen, David A1 - Risch, Lorenz A1 - Thériault, Sébastien A1 - Hutri-Kähönen, Nina A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Raitakari, Olli T A1 - Barnes, Catriona L K A1 - Campbell, Harry A1 - Joshi, Peter K A1 - Wilson, James F A1 - Isaacs, Aaron A1 - Kors, Jan A A1 - van Duijn, Cornelia M A1 - Huang, Paul L A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Nadkarni, Girish N A1 - Preuss, Michael H A1 - Correa, Adolfo A1 - Mei, Hao A1 - Wilson, James A1 - Meitinger, Thomas A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Rienstra, Michiel A1 - van de Vegte, Yordi J A1 - van der Harst, Pim A1 - Verweij, Niek A1 - Kääb, Stefan A1 - Schramm, Katharina A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Cutler, Michael J A1 - Fatkin, Diane A1 - London, Barry A1 - Olesen, Morten A1 - Roden, Dan M A1 - Benjamin Shoemaker, M A1 - Gustav Smith, J A1 - Biggs, Mary L A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Sotoodehnia, Nona A1 - De Grandi, Alessandro A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Ford, Ian A1 - Wouter Jukema, J A1 - Macfarlane, Peter W A1 - Trompet, Stella A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Völker, Uwe A1 - Weiss, Stefan A1 - Havulinna, Aki S A1 - Jula, Antti A1 - Sääksjärvi, Katri A1 - Salomaa, Veikko A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Lin, Henry J A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Yao, Jie A1 - de Mutsert, Renée A1 - Maan, Arie C A1 - Mook-Kanamori, Dennis O A1 - Noordam, Raymond A1 - Cucca, Francesco A1 - Ding, Jun A1 - Lakatta, Edward G A1 - Qian, Yong A1 - Tarasov, Kirill V A1 - Levy, Daniel A1 - Lin, Honghuang A1 - Newton-Cheh, Christopher H A1 - Lunetta, Kathryn L A1 - Murray, Alison D A1 - Porteous, David J A1 - Smith, Blair H A1 - Stricker, Bruno H A1 - Uitterlinden, Andre A1 - van den Berg, Marten E A1 - Haessler, Jeffrey A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Peters, Ulrike A1 - Reiner, Alexander P A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Gogarten, Stephanie M A1 - Kerr, Kathleen F A1 - Laurie, Cathy C A1 - Seyerle, Amanda A A1 - Stilp, Adrienne A1 - Assa, Solmaz A1 - Abdullah Said, M A1 - Yldau van der Ende, M A1 - Lambiase, Pier D A1 - Orini, Michele A1 - Ramirez, Julia A1 - Van Duijvenboden, Stefan A1 - Arnar, David O A1 - Gudbjartsson, Daniel F A1 - Holm, Hilma A1 - Sulem, Patrick A1 - Thorleifsson, Gudmar A1 - Thorolfsdottir, Rosa B A1 - Thorsteinsdottir, Unnur A1 - Benjamin, Emelia J A1 - Tinker, Andrew A1 - Stefansson, Kari A1 - Ellinor, Patrick T A1 - Jamshidi, Yalda A1 - Lubitz, Steven A A1 - Munroe, Patricia B AB -

The 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.

VL - 11 IS - 1 ER - TY - JOUR T1 - Patterns of Cardiovascular Risk Factors in Old Age and Survival and Health Status at 90. JF - J Gerontol A Biol Sci Med Sci Y1 - 2020 A1 - Odden, Michelle C A1 - Rawlings, Andreea M A1 - Arnold, Alice M A1 - Cushman, Mary A1 - Biggs, Mary L A1 - Psaty, Bruce M A1 - Newman, Anne B AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index. JF - JAMA Netw Open Y1 - 2020 A1 - Khera, Rohan A1 - Pandey, Ambarish A1 - Ayers, Colby R A1 - Carnethon, Mercedes R A1 - Greenland, Philip A1 - Ndumele, Chiadi E A1 - Nambi, Vijay A1 - Seliger, Stephen L A1 - Chaves, Paulo H M A1 - Safford, Monika M A1 - Cushman, Mary A1 - Xanthakis, Vanessa A1 - Vasan, Ramachandran S A1 - Mentz, Robert J A1 - Correa, Adolfo A1 - Lloyd-Jones, Donald M A1 - Berry, Jarett D A1 - de Lemos, James A A1 - Neeland, Ian J KW - Adult KW - Aged KW - Body Mass Index KW - Cardiovascular Diseases KW - Cohort Studies KW - Correlation of Data KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors AB -

Importance: 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.

VL - 3 IS - 10 ER - TY - JOUR T1 - Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2020 A1 - Jensen, Paul N A1 - Fretts, Amanda M A1 - Hoofnagle, Andrew N A1 - Sitlani, Colleen M A1 - McKnight, Barbara A1 - King, Irena B A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Mozaffarian, Dariush A1 - Sotoodehnia, Nona A1 - Lemaitre, Rozenn N AB -

Background 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.

VL - 9 IS - 4 ER - TY - JOUR T1 - The Polygenic and Monogenic Basis of Blood Traits and Diseases. JF - Cell Y1 - 2020 A1 - Vuckovic, Dragana A1 - Bao, Erik L A1 - Akbari, Parsa A1 - Lareau, Caleb A A1 - Mousas, Abdou A1 - Jiang, Tao A1 - Chen, Ming-Huei A1 - Raffield, Laura M A1 - Tardaguila, Manuel A1 - Huffman, Jennifer E A1 - Ritchie, Scott C A1 - Megy, Karyn A1 - Ponstingl, Hannes A1 - Penkett, Christopher J A1 - Albers, Patrick K A1 - Wigdor, Emilie M A1 - Sakaue, Saori A1 - Moscati, Arden A1 - Manansala, Regina A1 - Lo, Ken Sin A1 - Qian, Huijun A1 - Akiyama, Masato A1 - Bartz, Traci M A1 - Ben-Shlomo, Yoav A1 - Beswick, Andrew A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brody, Jennifer A A1 - van Rooij, Frank J A A1 - Chitrala, Kumaraswamy N A1 - Wilson, Peter W F A1 - Choquet, Helene A1 - Danesh, John A1 - Di Angelantonio, Emanuele A1 - Dimou, Niki A1 - Ding, Jingzhong A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Evans, Michele K A1 - Felix, Stephan B A1 - Floyd, James S A1 - Broer, Linda A1 - Grarup, Niels A1 - Guo, Michael H A1 - Guo, Qi A1 - Greinacher, Andreas A1 - Haessler, Jeff A1 - Hansen, Torben A1 - Howson, Joanna M M A1 - Huang, Wei A1 - Jorgenson, Eric A1 - Kacprowski, Tim A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Karthikeyan, Savita A1 - Koskeridis, Fotios A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Matsuda, Koichi A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Murakami, Yoshinori A1 - Nadkarni, Girish N A1 - Nikus, Kjell A1 - Pankratz, Nathan A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Rodriguez, Benjamin A T A1 - Rosen, Jonathan D A1 - Rotter, Jerome I A1 - Schubert, Petra A1 - Spracklen, Cassandra N A1 - Surendran, Praveen A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Ghanbari, Mohsen A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Nicholas A A1 - Weiss, Stefan A1 - Cai, Na A1 - Kundu, Kousik A1 - Watt, Stephen B A1 - Walter, Klaudia A1 - Zonderman, Alan B A1 - Cho, Kelly A1 - Li, Yun A1 - Loos, Ruth J F A1 - Knight, Julian C A1 - Georges, Michel A1 - Stegle, Oliver A1 - Evangelou, Evangelos A1 - Okada, Yukinori A1 - Roberts, David J A1 - Inouye, Michael A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Astle, William J A1 - Reiner, Alexander P A1 - Butterworth, Adam S A1 - Ouwehand, Willem H A1 - Lettre, Guillaume A1 - Sankaran, Vijay G A1 - Soranzo, Nicole AB -

Blood 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.

VL - 182 IS - 5 ER - TY - JOUR T1 - Predicting Risk of Atherosclerotic Cardiovascular Disease Using Pooled Cohort Equations in Older Adults With Frailty, Multimorbidity, and Competing Risks. JF - J Am Heart Assoc Y1 - 2020 A1 - Nguyen, Quoc Dinh A1 - Odden, Michelle C A1 - Peralta, Carmen A A1 - Kim, Dae Hyun AB -

Background 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.

VL - 9 IS - 18 ER - TY - JOUR T1 - Putative Cut-Points in Sarcopenia Components and Incident Adverse Health Outcomes: An SDOC Analysis. JF - J Am Geriatr Soc Y1 - 2020 A1 - Cawthon, Peggy M A1 - Manini, Todd A1 - Patel, Sheena M A1 - Newman, Anne A1 - Travison, Thomas A1 - Kiel, Douglas P A1 - Santanasto, Adam J A1 - Ensrud, Kristine E A1 - Xue, Qian-Li A1 - Shardell, Michelle A1 - Duchowny, Kate A1 - Erlandson, Kristine M A1 - Pencina, Karol M A1 - Fielding, Roger A A1 - Magaziner, Jay A1 - Kwok, Timothy A1 - Karlsson, Magnus A1 - Ohlsson, Claes A1 - Mellström, Dan A1 - Hirani, Vasant A1 - Ribom, Eva A1 - Correa-de-Araujo, Rosaly A1 - Bhasin, Shalender AB -

OBJECTIVES: 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.

VL - 68 IS - 7 ER - TY - JOUR T1 - Relation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients ≥ 65 Years of Age. JF - Am J Cardiol Y1 - 2020 A1 - Gottdiener, John S A1 - Seliger, Stephen A1 - DeFilippi, Christopher A1 - Christenson, Robert A1 - Baldridge, Abigail S A1 - Kizer, Jorge R A1 - Psaty, Bruce M A1 - Shah, Sanjiv J AB -

High 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.

ER - TY - JOUR T1 - Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. JF - Circ Genom Precis Med Y1 - 2020 A1 - Wang, Zhe A1 - Chen, Han A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chasman, Daniel I A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Lim, Elise A1 - Noordam, Raymond A1 - Richard, Melissa A A1 - Wang, Heming A1 - Cade, Brian A1 - Cupples, L Adrienne A1 - de Vries, Paul S A1 - Giulanini, Franco A1 - Lee, Jiwon A1 - Lemaitre, Rozenn N A1 - Martin, Lisa W A1 - Reiner, Alex P A1 - Rich, Stephen S A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Willems van Dijk, Ko A1 - Yao, Jie A1 - Zhao, Wei A1 - Fornage, Myriam A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Morrison, Alanna C AB -

BACKGROUND: 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.

VL - 13 IS - 4 ER - TY - JOUR T1 - Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure. JF - J Am Coll Cardiol Y1 - 2020 A1 - Suthahar, Navin A1 - Lau, Emily S A1 - Blaha, Michael J A1 - Paniagua, Samantha M A1 - Larson, Martin G A1 - Psaty, Bruce M A1 - Benjamin, Emelia J A1 - Allison, Matthew A A1 - Bartz, Traci M A1 - Januzzi, James L A1 - Levy, Daniel A1 - Meems, Laura M G A1 - Bakker, Stephan J L A1 - Lima, João A C A1 - Cushman, Mary A1 - Lee, Douglas S A1 - Wang, Thomas J A1 - deFilippi, Christopher R A1 - Herrington, David M A1 - Nayor, Matthew A1 - Vasan, Ramachandran S A1 - Gardin, Julius M A1 - Kizer, Jorge R A1 - Bertoni, Alain G A1 - Allen, Norrina B A1 - Gansevoort, Ron T A1 - Shah, Sanjiv J A1 - Gottdiener, John S A1 - Ho, Jennifer E A1 - de Boer, Rudolf A AB -

BACKGROUND: 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.

VL - 76 IS - 12 ER - TY - JOUR T1 - Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults. JF - J Card Fail Y1 - 2020 A1 - Al-Kindi, Sadeer G A1 - Bůzková, Petra A1 - Shitole, Sanyog G A1 - Reiner, Alex P A1 - Garg, Parveen K A1 - Gottdiener, John S A1 - Psaty, Bruce M A1 - Kizer, Jorge R AB -

BACKGROUND: 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.

VL - 26 IS - 5 ER - TY - JOUR T1 - A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber and reduced kidney function. JF - Kidney Int Y1 - 2020 A1 - Lye, Weng Kit A1 - Paterson, Euan A1 - Patterson, Christopher C A1 - Maxwell, Alexander P A1 - Binte Mohammed Abdul, Riswana Banu A1 - Tai, E Shyong A1 - Cheng, Ching Yu A1 - Kayama, Takamasa A1 - Yamashita, Hidetoshi A1 - Sarnak, Mark A1 - Shlipak, Michael A1 - Matsushita, Kunihiro A1 - Mutlu, Unal A1 - Ikram, Mohammad A A1 - Klaver, Caroline A1 - Kifley, Annette A1 - Mitchell, Paul A1 - Myers, Chelsea A1 - Klein, Barbara E A1 - Klein, Ronald A1 - Wong, Tien Y A1 - Sabanayagam, Charumathi A1 - McKay, Gareth J AB -

Previously, 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.

ER - TY - JOUR T1 - Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. JF - Cell Y1 - 2020 A1 - Chen, Ming-Huei A1 - Raffield, Laura M A1 - Mousas, Abdou A1 - Sakaue, Saori A1 - Huffman, Jennifer E A1 - Moscati, Arden A1 - Trivedi, Bhavi A1 - Jiang, Tao A1 - Akbari, Parsa A1 - Vuckovic, Dragana A1 - Bao, Erik L A1 - Zhong, Xue A1 - Manansala, Regina A1 - Laplante, Véronique A1 - Chen, Minhui A1 - Lo, Ken Sin A1 - Qian, Huijun A1 - Lareau, Caleb A A1 - Beaudoin, Mélissa A1 - Hunt, Karen A A1 - Akiyama, Masato A1 - Bartz, Traci M A1 - Ben-Shlomo, Yoav A1 - Beswick, Andrew A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brody, Jennifer A A1 - van Rooij, Frank J A A1 - Chitrala, Kumaraswamynaidu A1 - Cho, Kelly A1 - Choquet, Helene A1 - Correa, Adolfo A1 - Danesh, John A1 - Di Angelantonio, Emanuele A1 - Dimou, Niki A1 - Ding, Jingzhong A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Evans, Michele K A1 - Floyd, James S A1 - Broer, Linda A1 - Grarup, Niels A1 - Guo, Michael H A1 - Greinacher, Andreas A1 - Haessler, Jeff A1 - Hansen, Torben A1 - Howson, Joanna M M A1 - Huang, Qin Qin A1 - Huang, Wei A1 - Jorgenson, Eric A1 - Kacprowski, Tim A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Karthikeyan, Savita A1 - Koskeridis, Fotis A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Lerch, Markus M A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Martin, Hilary C A1 - Matsuda, Koichi A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Murakami, Yoshinori A1 - Nadkarni, Girish N A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ouwehand, Willem H A1 - Pankratz, Nathan A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Roberts, David J A1 - Rich, Stephen S A1 - Rodriguez, Benjamin A T A1 - Rosen, Jonathan D A1 - Rotter, Jerome I A1 - Schubert, Petra A1 - Spracklen, Cassandra N A1 - Surendran, Praveen A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Trembath, Richard C A1 - Ghanbari, Mohsen A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Nicholas A A1 - Zonderman, Alan B A1 - Wilson, Peter W F A1 - Li, Yun A1 - Butterworth, Adam S A1 - Gauchat, Jean-François A1 - Chiang, Charleston W K A1 - Li, Bingshan A1 - Loos, Ruth J F A1 - Astle, William J A1 - Evangelou, Evangelos A1 - van Heel, David A A1 - Sankaran, Vijay G A1 - Okada, Yukinori A1 - Soranzo, Nicole A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Auer, Paul L A1 - Lettre, Guillaume AB -

Most 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.

VL - 182 IS - 5 ER - TY - JOUR T1 - Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. JF - Circ Genom Precis Med Y1 - 2020 A1 - Ma, Jiantao A1 - Rebholz, Casey M A1 - Braun, Kim V E A1 - Reynolds, Lindsay M A1 - Aslibekyan, Stella A1 - Xia, Rui A1 - Biligowda, Niranjan G A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Joehanes, Roby A1 - Hu, Emily A A1 - Vitolins, Mara Z A1 - Wood, Alexis C A1 - Lohman, Kurt A1 - Ochoa-Rosales, Carolina A1 - van Meurs, Joyce A1 - Uitterlinden, Andre A1 - Liu, Yongmei A1 - Elhadad, Mohamed A A1 - Heier, Margit A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Colicino, Elena A1 - Whitsel, Eric A A1 - Baldassari, Antoine A1 - Gharib, Sina A A1 - Sotoodehnia, Nona A1 - Brody, Jennifer A A1 - Sitlani, Colleen M A1 - Tanaka, Toshiko A1 - Hill, W David A1 - Corley, Janie A1 - Deary, Ian J A1 - Zhang, Yan A1 - Schöttker, Ben A1 - Brenner, Hermann A1 - Walker, Maura E A1 - Ye, Shumao A1 - Nguyen, Steve A1 - Pankow, Jim A1 - Demerath, Ellen W A1 - Zheng, Yinan A1 - Hou, Lifang A1 - Liang, Liming A1 - Lichtenstein, Alice H A1 - Hu, Frank B A1 - Fornage, Myriam A1 - Voortman, Trudy A1 - Levy, Daniel AB -

BACKGROUND: 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.

VL - 13 IS - 4 ER - TY - JOUR T1 - Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. JF - Nat Commun Y1 - 2020 A1 - Zhao, Xutong A1 - Qiao, Dandi A1 - Yang, Chaojie A1 - Kasela, Silva A1 - Kim, Wonji A1 - Ma, Yanlin A1 - Shrine, Nick A1 - Batini, Chiara A1 - Sofer, Tamar A1 - Taliun, Sarah A Gagliano A1 - Sakornsakolpat, Phuwanat A1 - Balte, Pallavi P A1 - Prokopenko, Dmitry A1 - Yu, Bing A1 - Lange, Leslie A A1 - Dupuis, Josée A1 - Cade, Brian E A1 - Lee, Jiwon A1 - Gharib, Sina A A1 - Daya, Michelle A1 - Laurie, Cecelia A A1 - Ruczinski, Ingo A1 - Cupples, L Adrienne A1 - Loehr, Laura R A1 - Bartz, Traci M A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Taylor, Kent D A1 - Durda, Peter A1 - Johnson, W Craig A1 - Cornell, Elaine A1 - Guo, Xiuqing A1 - Liu, Yongmei A1 - Tracy, Russell P A1 - Ardlie, Kristin G A1 - Aguet, Francois A1 - VanDenBerg, David J A1 - Papanicolaou, George J A1 - Rotter, Jerome I A1 - Barnes, Kathleen C A1 - Jain, Deepti A1 - Nickerson, Deborah A A1 - Muzny, Donna M A1 - Metcalf, Ginger A A1 - Doddapaneni, Harshavardhan A1 - Dugan-Perez, Shannon A1 - Gupta, Namrata A1 - Gabriel, Stacey A1 - Rich, Stephen S A1 - O'Connor, George T A1 - Redline, Susan A1 - Reed, Robert M A1 - Laurie, Cathy C A1 - Daviglus, Martha L A1 - Preudhomme, Liana K A1 - Burkart, Kristin M A1 - Kaplan, Robert C A1 - Wain, Louise V A1 - Tobin, Martin D A1 - London, Stephanie J A1 - Lappalainen, Tuuli A1 - Oelsner, Elizabeth C A1 - Abecasis, Goncalo R A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Cho, Michael H A1 - Manichaikul, Ani KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Calcium-Binding Proteins KW - Feasibility Studies KW - Female KW - Follow-Up Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Lung KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Inhibitors of Activated STAT KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Physiological Phenomena KW - Small Ubiquitin-Related Modifier Proteins KW - Whole Genome Sequencing AB -

Chronic 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.

VL - 11 IS - 1 ER - TY - JOUR T1 - Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study. JF - Heart Y1 - 2021 A1 - Massera, Daniele A1 - Hu, Mo A1 - Delaney, Joseph A A1 - Bartz, Traci M A1 - Bach, Megan E A1 - Dvorak, Stephen J A1 - deFilippi, Christopher R A1 - Psaty, Bruce M A1 - Gottdiener, John S A1 - Kizer, Jorge R A1 - Shah, Sanjiv J AB -

OBJECTIVES: 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.

ER - TY - JOUR T1 - Association Between Myocardial Strain and Frailty in CHS. JF - Circ Cardiovasc Imaging Y1 - 2021 A1 - Tan, Annabel X A1 - Shah, Sanjiv J A1 - Sanders, Jason L A1 - Psaty, Bruce M A1 - Wu, Chenkai A1 - Gardin, Julius M A1 - Peralta, Carmen A A1 - Newman, Anne B A1 - Odden, Michelle C AB -

BACKGROUND: 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.

VL - 14 IS - 5 ER - TY - JOUR T1 - Association of low-frequency and rare coding variants with information processing speed. JF - Transl Psychiatry Y1 - 2021 A1 - Bressler, Jan A1 - Davies, Gail A1 - Smith, Albert V A1 - Saba, Yasaman A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Hayward, Caroline A1 - Yanek, Lisa A1 - Smith, Jennifer A A1 - Mirza, Saira S A1 - Wang, Ruiqi A1 - Adams, Hieab H H A1 - Becker, Diane A1 - Boerwinkle, Eric A1 - Campbell, Archie A1 - Cox, Simon R A1 - Eiriksdottir, Gudny A1 - Fawns-Ritchie, Chloe A1 - Gottesman, Rebecca F A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Kardia, Sharon L R A1 - Knol, Maria J A1 - Koini, Marisa A1 - Lopez, Oscar L A1 - Marioni, Riccardo E A1 - Nyquist, Paul A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rudan, Igor A1 - Satizabal, Claudia L A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Sidney, Stephen A1 - Simino, Jeannette A1 - Smith, Blair H A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Whitmer, Rachel A A1 - Yaffe, Kristine A1 - Yang, Qiong A1 - Zhao, Wei A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Fitzpatrick, Annette L A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Arfan Ikram, M A1 - van Duijn, Cornelia M A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Deary, Ian J KW - Adult KW - Aging KW - Cognition KW - Genome-Wide Association Study KW - Geroscience KW - Humans KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

Measures 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.

VL - 11 IS - 1 ER - TY - JOUR T1 - Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life. JF - J Card Fail Y1 - 2021 A1 - Cohen, Laura P A1 - Vittinghoff, Eric A1 - Pletcher, Mark J A1 - Allen, Norrina B A1 - Shah, Sanjiv J A1 - Wilkins, John T A1 - Chang, Patricia P A1 - Ndumele, Chiadi E A1 - Newman, Anne B A1 - Ives, Diane A1 - Maurer, Mathew S A1 - Oelsner, Elizabeth C A1 - Moran, Andrew E A1 - Zhang, Yiyi AB -

BACKGROUND: 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.

VL - 27 IS - 4 ER - TY - JOUR T1 - Association of mitochondrial DNA copy number with cardiometabolic diseases. JF - Cell Genom Y1 - 2021 A1 - Liu, Xue A1 - Longchamps, Ryan J A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Kurniansyah, Nuzulul A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Cupples, L Adrienne A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Sofer, Tamar A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Correa, Adolfo A1 - Abecasis, Goncalo A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Mitochondrial 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.

VL - 1 IS - 1 ER - TY - JOUR T1 - Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease. JF - Alzheimers Dement Y1 - 2021 A1 - Zhang, Xiaoling A1 - Farrell, John J A1 - Tong, Tong A1 - Hu, Junming A1 - Zhu, Congcong A1 - Wang, Li-San A1 - Mayeux, Richard A1 - Haines, Jonathan L A1 - Pericak-Vance, Margaret A A1 - Schellenberg, Gerard D A1 - Lunetta, Kathryn L A1 - Farrer, Lindsay A AB -

INTRODUCTION: 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.

ER - TY - JOUR T1 - Association of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study. JF - JAMA Netw Open Y1 - 2021 A1 - Lemaitre, Rozenn N A1 - Jensen, Paul N A1 - Wang, Zeneng A1 - Fretts, Amanda M A1 - McKnight, Barbara A1 - Nemet, Ina A1 - Biggs, Mary L A1 - Sotoodehnia, Nona A1 - de Oliveira Otto, Marcia C A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Hazen, Stanley L A1 - Mozaffarian, Dariush AB -

Importance: 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.

VL - 4 IS - 8 ER - TY - JOUR T1 - Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes. JF - J Clin Endocrinol Metab Y1 - 2021 A1 - Nair, Nandini A1 - Vittinghoff, Eric A1 - Pletcher, Mark J A1 - Oelsner, Elizabeth C A1 - Allen, Norrina B A1 - Ndumele, Chiadi E A1 - West, Nancy A A1 - Strotmeyer, Elsa S A1 - Mukamal, Kenneth J A1 - Siscovick, David S A1 - Biggs, Mary L A1 - Laferrère, Blandine A1 - Moran, Andrew E A1 - Zhang, Yiyi KW - Adolescent KW - Adult KW - Biomarkers KW - Body Mass Index KW - Diabetes Mellitus KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Obesity KW - Overweight KW - Prognosis KW - Prospective Studies KW - Risk Factors KW - United States KW - Waist Circumference KW - Young Adult AB -

CONTEXT: 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.

VL - 106 IS - 12 ER - TY - JOUR T1 - BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion. JF - HGG Adv Y1 - 2021 A1 - Sofer, Tamar A1 - Lee, Jiwon A1 - Kurniansyah, Nuzulul A1 - Jain, Deepti A1 - Laurie, Cecelia A A1 - Gogarten, Stephanie M A1 - Conomos, Matthew P A1 - Heavner, Ben A1 - Hu, Yao A1 - Kooperberg, Charles A1 - Haessler, Jeffrey A1 - Vasan, Ramachandran S A1 - Cupples, L Adrienne A1 - Coombes, Brandon J A1 - Seyerle, Amanda A1 - Gharib, Sina A A1 - Chen, Han A1 - O'Connell, Jeffrey R A1 - Zhang, Man A1 - Gottlieb, Daniel J A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Boerwinkle, Eric A1 - Morrison, Alanna C A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Pankratz, Nathan A1 - Reiner, Alex P A1 - Redline, Susan A1 - Smith, Nicholas L A1 - Rice, Kenneth M A1 - Schifano, Elizabeth D AB -

Whole-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.

VL - 2 IS - 3 ER - TY - JOUR T1 - Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. JF - Nat Commun Y1 - 2021 A1 - Harris, William S A1 - Tintle, Nathan L A1 - Imamura, Fumiaki A1 - Qian, Frank A1 - Korat, Andres V Ardisson A1 - Marklund, Matti A1 - Djoussé, Luc A1 - Bassett, Julie K A1 - Carmichael, Pierre-Hugues A1 - Chen, Yun-Yu A1 - Hirakawa, Yoichiro A1 - Küpers, Leanne K A1 - Laguzzi, Federica A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Samieri, Cecilia A1 - Senn, Mackenzie K A1 - Shi, Peilin A1 - Virtanen, Jyrki K A1 - Brouwer, Ingeborg A A1 - Chien, Kuo-Liong A1 - Eiriksdottir, Gudny A1 - Forouhi, Nita G A1 - Geleijnse, Johanna M A1 - Giles, Graham G A1 - Gudnason, Vilmundur A1 - Helmer, Catherine A1 - Hodge, Allison A1 - Jackson, Rebecca A1 - Khaw, Kay-Tee A1 - Laakso, Markku A1 - Lai, Heidi A1 - Laurin, Danielle A1 - Leander, Karin A1 - Lindsay, Joan A1 - Micha, Renata A1 - Mursu, Jaako A1 - Ninomiya, Toshiharu A1 - Post, Wendy A1 - Psaty, Bruce M A1 - Riserus, Ulf A1 - Robinson, Jennifer G A1 - Shadyab, Aladdin H A1 - Snetselaar, Linda A1 - Sala-Vila, Aleix A1 - Sun, Yangbo A1 - Steffen, Lyn M A1 - Tsai, Michael Y A1 - Wareham, Nicholas J A1 - Wood, Alexis C A1 - Wu, Jason H Y A1 - Hu, Frank A1 - Sun, Qi A1 - Siscovick, David S A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Fatty Acids, Omega-3 KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Middle Aged KW - Mortality, Premature KW - Prospective Studies KW - Protective Factors KW - Risk Factors AB -

The 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. JF - Nat Commun Y1 - 2021 A1 - Natarajan, Pradeep A1 - Pampana, Akhil A1 - Graham, Sarah E A1 - Ruotsalainen, Sanni E A1 - Perry, James A A1 - de Vries, Paul S A1 - Broome, Jai G A1 - Pirruccello, James P A1 - Honigberg, Michael C A1 - Aragam, Krishna A1 - Wolford, Brooke A1 - Brody, Jennifer A A1 - Antonacci-Fulton, Lucinda A1 - Arden, Moscati A1 - Aslibekyan, Stella A1 - Assimes, Themistocles L A1 - Ballantyne, Christie M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Do, Ron A1 - Doddapaneni, Harsha A1 - Emery, Leslie S A1 - Hung, Yi-Jen A1 - Irvin, Marguerite R A1 - Khan, Alyna T A1 - Lange, Leslie A1 - Lee, Jiwon A1 - Lemaitre, Rozenn N A1 - Martin, Lisa W A1 - Metcalf, Ginger A1 - Montasser, May E A1 - Moon, Jee-Young A1 - Muzny, Donna A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Stilp, Adrienne M A1 - Tsai, Michael A1 - Wang, Fei Fei A1 - Weeks, Daniel E A1 - Yanek, Lisa R A1 - Wilson, James G A1 - Abecasis, Goncalo A1 - Arnett, Donna K A1 - Becker, Lewis C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Chang, Yi-Cheng A1 - Chen, Yii-der I A1 - Choi, Won Jung A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Daly, Mark J A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A A1 - He, Jiang A1 - Hveem, Kristian A1 - Jarvik, Gail P A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kenny, Eimear A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Lee, Seonwook A1 - Lloyd-Jones, Don M A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Mathias, Rasika A A1 - Martinez, Karine A Viaud A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Nickerson, Deborah A A1 - North, Kari E A1 - Palotie, Aarno A1 - Park, Cheol Joo A1 - Psaty, Bruce M A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Seo, Daekwan A1 - Seo, Jeong-Sun A1 - Smith, Albert V A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - Morrison, Alanna C A1 - Rich, Stephen S A1 - Ripatti, Samuli A1 - Willer, Cristen A1 - Peloso, Gina M AB -

Autosomal 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study. JF - Clin Chem Y1 - 2021 A1 - Fretts, Amanda M A1 - Jensen, Paul N A1 - Hoofnagle, Andrew N A1 - McKnight, Barbara A1 - Sitlani, Colleen M A1 - Siscovick, David S A1 - King, Irena B A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Lemaitre, Rozenn N AB -

BACKGROUND: 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.

VL - 67 IS - 12 ER - TY - JOUR T1 - Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults. JF - Heart Y1 - 2021 A1 - Owens, David S A1 - Bartz, Traci M A1 - Bůzková, Petra A1 - Massera, Daniele A1 - Biggs, Mary L A1 - Carlson, Selma D A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Gottdiener, John S A1 - Kizer, Jorge R AB -

OBJECTIVES: 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.

ER - TY - JOUR T1 - Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. JF - Nat Commun Y1 - 2021 A1 - Goodrich, Julia K A1 - Singer-Berk, Moriel A1 - Son, Rachel A1 - Sveden, Abigail A1 - Wood, Jordan A1 - England, Eleina A1 - Cole, Joanne B A1 - Weisburd, Ben A1 - Watts, Nick A1 - Caulkins, Lizz A1 - Dornbos, Peter A1 - Koesterer, Ryan A1 - Zappala, Zachary A1 - Zhang, Haichen A1 - Maloney, Kristin A A1 - Dahl, Andy A1 - Aguilar-Salinas, Carlos A A1 - Atzmon, Gil A1 - Barajas-Olmos, Francisco A1 - Barzilai, Nir A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bottinger, Erwin A1 - Bowden, Donald W A1 - Centeno-Cruz, Federico A1 - Chambers, John C A1 - Chami, Nathalie A1 - Chan, Edmund A1 - Chan, Juliana A1 - Cheng, Ching-Yu A1 - Cho, Yoon Shin A1 - Contreras-Cubas, Cecilia A1 - Córdova, Emilio A1 - Correa, Adolfo A1 - DeFronzo, Ralph A A1 - Duggirala, Ravindranath A1 - Dupuis, Josée A1 - Garay-Sevilla, Ma Eugenia A1 - García-Ortiz, Humberto A1 - Gieger, Christian A1 - Glaser, Benjamin A1 - González-Villalpando, Clicerio A1 - Gonzalez, Ma Elena A1 - Grarup, Niels A1 - Groop, Leif A1 - Gross, Myron A1 - Haiman, Christopher A1 - Han, Sohee A1 - Hanis, Craig L A1 - Hansen, Torben A1 - Heard-Costa, Nancy L A1 - Henderson, Brian E A1 - Hernandez, Juan Manuel Malacara A1 - Hwang, Mi Yeong A1 - Islas-Andrade, Sergio A1 - Jørgensen, Marit E A1 - Kang, Hyun Min A1 - Kim, Bong-Jo A1 - Kim, Young Jin A1 - Koistinen, Heikki A A1 - Kooner, Jaspal Singh A1 - Kuusisto, Johanna A1 - Kwak, Soo-Heon A1 - Laakso, Markku A1 - Lange, Leslie A1 - Lee, Jong-Young A1 - Lee, Juyoung A1 - Lehman, Donna M A1 - Linneberg, Allan A1 - Liu, Jianjun A1 - Loos, Ruth J F A1 - Lyssenko, Valeriya A1 - Ma, Ronald C W A1 - Martínez-Hernández, Angélica A1 - Meigs, James B A1 - Meitinger, Thomas A1 - Mendoza-Caamal, Elvia A1 - Mohlke, Karen L A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Ng, Maggie C Y A1 - Nilsson, Peter M A1 - O'Donnell, Christopher J A1 - Orozco, Lorena A1 - Palmer, Colin N A A1 - Park, Kyong Soo A1 - Post, Wendy S A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Reiner, Alexander P A1 - Revilla-Monsalve, Cristina A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Saleheen, Danish A1 - Schurmann, Claudia A1 - Sim, Xueling A1 - Sladek, Rob A1 - Small, Kerrin S A1 - So, Wing Yee A1 - Spector, Timothy D A1 - Strauch, Konstantin A1 - Strom, Tim M A1 - Tai, E Shyong A1 - Tam, Claudia H T A1 - Teo, Yik Ying A1 - Thameem, Farook A1 - Tomlinson, Brian A1 - Tracy, Russell P A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - van Dam, Rob M A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Witte, Daniel R A1 - Wong, Tien-Yin A1 - Burtt, Noel P A1 - Zaitlen, Noah A1 - McCarthy, Mark I A1 - Boehnke, Michael A1 - Pollin, Toni I A1 - Flannick, Jason A1 - Mercader, Josep M A1 - O'Donnell-Luria, Anne A1 - Baxter, Samantha A1 - Florez, Jose C A1 - MacArthur, Daniel G A1 - Udler, Miriam S KW - Adult KW - Biological Variation, Population KW - Biomarkers KW - Diabetes Mellitus, Type 2 KW - Dyslipidemias KW - Exome KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Multifactorial Inheritance KW - Penetrance KW - Risk Assessment AB -

Hundreds 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. JF - Am J Hum Genet Y1 - 2021 A1 - Graff, Mariaelisa A1 - Justice, Anne E A1 - Young, Kristin L A1 - Marouli, Eirini A1 - Zhang, Xinruo A1 - Fine, Rebecca S A1 - Lim, Elise A1 - Buchanan, Victoria A1 - Rand, Kristin A1 - Feitosa, Mary F A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Shao, Yaming A1 - Rohde, Rebecca A1 - Adeyemo, Adebowale A A1 - Aldrich, Melinda C A1 - Allison, Matthew A A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Amos, Christopher A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Bandera, Elisa V A1 - Bartz, Traci A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Bielak, Lawrence F A1 - Blot, William J A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Burke, Gregory A1 - Cade, Brian E A1 - Cai, Qiuyin A1 - Caporaso, Neil A1 - Carlson, Chris A1 - Carpten, John A1 - Casey, Graham A1 - Chanock, Stephen J A1 - Chen, Guanjie A1 - Chen, Minhui A1 - Chen, Yii-der I A1 - Chen, Wei-Min A1 - Chesi, Alessandra A1 - Chiang, Charleston W K A1 - Chu, Lisa A1 - Coetzee, Gerry A A1 - Conti, David V A1 - Cooper, Richard S A1 - Cushman, Mary A1 - Demerath, Ellen A1 - Deming, Sandra L A1 - Dimitrov, Latchezar A1 - Ding, Jingzhong A1 - Diver, W Ryan A1 - Duan, Qing A1 - Evans, Michele K A1 - Falusi, Adeyinka G A1 - Faul, Jessica D A1 - Fornage, Myriam A1 - Fox, Caroline A1 - Freedman, Barry I A1 - Garcia, Melissa A1 - Gillanders, Elizabeth M A1 - Goodman, Phyllis A1 - Gottesman, Omri A1 - Grant, Struan F A A1 - Guo, Xiuqing A1 - Hakonarson, Hakon A1 - Haritunians, Talin A1 - Harris, Tamara B A1 - Harris, Curtis C A1 - Henderson, Brian E A1 - Hennis, Anselm A1 - Hernandez, Dena G A1 - Hirschhorn, Joel N A1 - McNeill, Lorna Haughton A1 - Howard, Timothy D A1 - Howard, Barbara A1 - Hsing, Ann W A1 - Hsu, Yu-Han H A1 - Hu, Jennifer J A1 - Huff, Chad D A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - Irvin, Marguerite R A1 - John, Esther M A1 - Johnson, Karen C A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kang, Sun J A1 - Kardia, Sharon L A1 - Keating, Brendan J A1 - Kittles, Rick A A1 - Klein, Eric A A1 - Kolb, Suzanne A1 - Kolonel, Laurence N A1 - Kooperberg, Charles A1 - Kuller, Lewis A1 - Kutlar, Abdullah A1 - Lange, Leslie A1 - Langefeld, Carl D A1 - Le Marchand, Loïc A1 - Leonard, Hampton A1 - Lettre, Guillaume A1 - Levin, Albert M A1 - Li, Yun A1 - Li, Jin A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Liu, Simin A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lu, Yingchang A1 - Maixner, William A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Meng, Yan A1 - Monda, Keri L A1 - Monroe, Kris A1 - Moore, Jason H A1 - Mosley, Thomas H A1 - Mudgal, Poorva A1 - Murphy, Adam B A1 - Nadukuru, Rajiv A1 - Nalls, Mike A A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian L A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogundiran, Temidayo O A1 - Ogunniyi, Adesola A1 - Ojengbede, Oladosu A1 - Okut, Hayrettin A1 - Olopade, Olufunmilayo I A1 - Olshan, Andrew A1 - Padhukasahasram, Badri A1 - Palmer, Julie A1 - Palmer, Cameron D A1 - Palmer, Nicholette D A1 - Papanicolaou, George A1 - Patel, Sanjay R A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Press, Michael F A1 - Rao, D C A1 - Rasmussen-Torvik, Laura J A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rhie, Suhn K A1 - Rodriguez-Gil, Jorge L A1 - Rotimi, Charles N A1 - Rotter, Jerome I A1 - Ruiz-Narvaez, Edward A A1 - Rybicki, Benjamin A A1 - Salako, Babatunde A1 - Sale, Michèle M A1 - Sanderson, Maureen A1 - Schadt, Eric A1 - Schreiner, Pamela J A1 - Schurmann, Claudia A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Siscovick, David S A1 - Smith, Jennifer A A1 - Smith, Shad A1 - Speliotes, Elizabeth A1 - Spitz, Margaret A1 - Stanford, Janet L A1 - Stevens, Victoria L A1 - Stram, Alex A1 - Strom, Sara S A1 - Sucheston, Lara A1 - Sun, Yan V A1 - Tajuddin, Salman M A1 - Taylor, Herman A1 - Taylor, Kira A1 - Tayo, Bamidele O A1 - Thun, Michael J A1 - Tucker, Margaret A A1 - Vaidya, Dhananjay A1 - Van Den Berg, David J A1 - Vedantam, Sailaja A1 - Vitolins, Mara A1 - Wang, Zhaoming A1 - Ware, Erin B A1 - Wassertheil-Smoller, Sylvia A1 - Weir, David R A1 - Wiencke, John K A1 - Williams, Scott M A1 - Williams, L Keoki A1 - Wilson, James G A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yao, Jie A1 - Zakai, Neil A1 - Zanetti, Krista A1 - Zemel, Babette S A1 - Zhao, Wei A1 - Zhao, Jing Hua A1 - Zheng, Wei A1 - Zhi, Degui A1 - Zhou, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Regina G A1 - Zmuda, Joe A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Liu, Ching-Ti A1 - Haiman, Christopher A A1 - Loos, Ruth A1 - Ng, Maggie C Y A1 - North, Kari E AB -

Although 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.

VL - 108 IS - 4 ER - TY - JOUR T1 - Epigenetic Age and the Risk of Incident Atrial Fibrillation. JF - Circulation Y1 - 2021 A1 - Roberts, Jason D A1 - Vittinghoff, Eric A1 - Lu, Ake T A1 - Alonso, Alvaro A1 - Wang, Biqi A1 - Sitlani, Colleen M A1 - Mohammadi-Shemirani, Pedrum A1 - Fornage, Myriam A1 - Kornej, Jelena A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Lin, Honghuang A1 - Heckbert, Susan R A1 - Prokic, Ivana A1 - Ghanbari, Mohsen A1 - Skanes, Allan C A1 - Bartz, Traci M A1 - Perez, Marco V A1 - Taylor, Kent D A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Pankow, James S A1 - Paré, Guillaume A1 - Sotoodehnia, Nona A1 - Benjamin, Emelia J A1 - Horvath, Steve A1 - Marcus, Gregory M KW - Aged KW - Aging KW - Atrial Fibrillation KW - DNA Methylation KW - Epigenesis, Genetic KW - Epigenomics KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Cardiovascular KW - Models, Genetic AB -

BACKGROUND: 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.

VL - 144 IS - 24 ER - TY - JOUR T1 - {Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption JF - Nat Commun Y1 - 2021 A1 - Karabegović, I. A1 - Portilla-Fernandez, E. A1 - Li, Y. A1 - Ma, J. A1 - Maas, S. C. E. A1 - Sun, D. A1 - Hu, E. A. A1 - Kühnel, B. A1 - Zhang, Y. A1 - Ambatipudi, S. A1 - Fiorito, G. A1 - Huang, J. A1 - Castillo-Fernandez, J. E. A1 - Wiggins, K. L. A1 - de Klein, N. A1 - Grioni, S. A1 - Swenson, B. R. A1 - Polidoro, S. A1 - Treur, J. L. A1 - Cuenin, C. A1 - Tsai, P. C. A1 - Costeira, R. A1 - Chajes, V. A1 - Braun, K. A1 - Verweij, N. A1 - Kretschmer, A. A1 - Franke, L. A1 - van Meurs, J. B. J. A1 - Uitterlinden, A. G. A1 - de Knegt, R. J. A1 - Ikram, M. A. A1 - Dehghan, A. A1 - Peters, A. A1 - Schöttker, B. A1 - Gharib, S. A. A1 - Sotoodehnia, N. A1 - Bell, J. T. A1 - Elliott, P. A1 - Vineis, P. A1 - Relton, C. A1 - Herceg, Z. A1 - Brenner, H. A1 - Waldenberger, M. A1 - Rebholz, C. M. A1 - Voortman, T. A1 - Pan, Q. A1 - Fornage, M. A1 - Levy, D. A1 - Kayser, M. A1 - Ghanbari, M. AB - 10.1038/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. VL - 12 ER - TY - JOUR T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JF - Nat Commun Y1 - 2021 A1 - Tin, Adrienne A1 - Schlosser, Pascal A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Yu, Zhi A1 - Weihs, Antoine A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Kuhns, Victoria L Halperin A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Bressler, Jan A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - Delgado, Graciela E A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Floyd, James S A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Gelber, Allan C A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Ladd-Acosta, Christine A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Lloyd-Jones, Donald M A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Völker, Uwe A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Waldenberger, Melanie A1 - Levy, Daniel A1 - Akilesh, Shreeram A1 - Woodward, Owen M A1 - Susztak, Katalin A1 - Teumer, Alexander A1 - Köttgen, Anna KW - Amino Acid Transport System y+ KW - Cohort Studies KW - CpG Islands KW - DNA Methylation KW - Epigenome KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Transport Proteins, Facilitative KW - Gout KW - Humans KW - Male KW - Uric Acid AB -

Elevated 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer. JF - J Thromb Haemost Y1 - 2021 A1 - Thibord, Florian A1 - Song, Ci A1 - Pattee, Jack A1 - Rodriguez, Benjamin A T A1 - Chen, Ming-Huei A1 - O'Donnell, Christopher J A1 - Kleber, Marcus E A1 - Delgado, Graciela E A1 - Guo, Xiuqing A1 - Yao, Jie A1 - Taylor, Kent D A1 - Ozel, Ayse Bilge A1 - Brody, Jennifer A A1 - McKnight, Barbara A1 - Gyorgy, Beata A1 - Simonsick, Eleanor A1 - Leonard, Hampton L A1 - Carrasquilla, Germán D A1 - Guindo-Martinez, Marta A1 - Silveira, Angela A1 - Temprano-Sagrera, Gerard A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Mathias, Rasika A A1 - Becker, Lewis C A1 - Raffield, Laura M A1 - Kilpeläinen, Tuomas O A1 - Grarup, Niels A1 - Pedersen, Oluf A1 - Hansen, Torben A1 - Linneberg, Allan A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Sabater-Lleal, Maria A1 - Nalls, Mike A A1 - Trégouët, David-Alexandre A1 - Morange, Pierre-Emmanuel A1 - Psaty, Bruce M A1 - Tracy, Russel P A1 - Smith, Nicholas L A1 - Desch, Karl C A1 - Cushman, Mary A1 - Rotter, Jerome I A1 - de Vries, Paul S A1 - Pankratz, Nathan D A1 - Folsom, Aaron R A1 - Morrison, Alanna C A1 - März, Winfried A1 - Tang, Weihong A1 - Johnson, Andrew D AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Genetic insights into biological mechanisms governing human ovarian ageing. JF - Nature Y1 - 2021 A1 - Ruth, Katherine S A1 - Day, Felix R A1 - Hussain, Jazib A1 - Martínez-Marchal, Ana A1 - Aiken, Catherine E A1 - Azad, Ajuna A1 - Thompson, Deborah J A1 - Knoblochova, Lucie A1 - Abe, Hironori A1 - Tarry-Adkins, Jane L A1 - Gonzalez, Javier Martin A1 - Fontanillas, Pierre A1 - Claringbould, Annique A1 - Bakker, Olivier B A1 - Sulem, Patrick A1 - Walters, Robin G A1 - Terao, Chikashi A1 - Turon, Sandra A1 - Horikoshi, Momoko A1 - Lin, Kuang A1 - Onland-Moret, N Charlotte A1 - Sankar, Aditya A1 - Hertz, Emil Peter Thrane A1 - Timshel, Pascal N A1 - Shukla, Vallari A1 - Borup, Rehannah A1 - Olsen, Kristina W A1 - Aguilera, Paula A1 - Ferrer-Roda, Mònica A1 - Huang, Yan A1 - Stankovic, Stasa A1 - Timmers, Paul R H J A1 - Ahearn, Thomas U A1 - Alizadeh, Behrooz Z A1 - Naderi, Elnaz A1 - Andrulis, Irene L A1 - Arnold, Alice M A1 - Aronson, Kristan J A1 - Augustinsson, Annelie A1 - Bandinelli, Stefania A1 - Barbieri, Caterina M A1 - Beaumont, Robin N A1 - Becher, Heiko A1 - Beckmann, Matthias W A1 - Benonisdottir, Stefania A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Boomsma, Dorret I A1 - Bowker, Nicholas A1 - Brody, Jennifer A A1 - Broer, Linda A1 - Buring, Julie E A1 - Campbell, Archie A1 - Campbell, Harry A1 - Castelao, Jose E A1 - Catamo, Eulalia A1 - Chanock, Stephen J A1 - Chenevix-Trench, Georgia A1 - Ciullo, Marina A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cox, Angela A1 - Crisponi, Laura A1 - Cross, Simon S A1 - Cucca, Francesco A1 - Czene, Kamila A1 - Smith, George Davey A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Dunning, Alison M A1 - Dwek, Miriam A1 - Eriksson, Mikael A1 - Esko, Tõnu A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Ferrucci, Luigi A1 - Franceschini, Nora A1 - Frayling, Timothy M A1 - Gago-Dominguez, Manuela A1 - Mezzavilla, Massimo A1 - García-Closas, Montserrat A1 - Gieger, Christian A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guénel, Pascal A1 - Haiman, Christopher A A1 - Håkansson, Niclas A1 - Hall, Per A1 - Hayward, Caroline A1 - He, Chunyan A1 - He, Wei A1 - Heiss, Gerardo A1 - Høffding, Miya K A1 - Hopper, John L A1 - Hottenga, Jouke J A1 - Hu, Frank A1 - Hunter, David A1 - Ikram, Mohammad A A1 - Jackson, Rebecca D A1 - Joaquim, Micaella D R A1 - John, Esther M A1 - Joshi, Peter K A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Kartsonaki, Christiana A1 - Karlsson, Robert A1 - Kitahara, Cari M A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kraft, Peter A1 - Kurian, Allison W A1 - Kutalik, Zoltán A1 - La Bianca, Martina A1 - Lachance, Genevieve A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lawlor, Deborah A A1 - Le Marchand, Loïc A1 - Li, Jingmei A1 - Lindblom, Annika A1 - Lindström, Sara A1 - Lindstrom, Tricia A1 - Linet, Martha A1 - Liu, Yongmei A1 - Liu, Simin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mannermaa, Arto A1 - Marco, Brumat A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mbarek, Hamdi A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mulas, Antonella A1 - Mulligan, Anna M A1 - Murray, Alison A1 - Nalls, Mike A A1 - Newman, Anne A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Nyholt, Dale R A1 - Olshan, Andrew F A1 - Olsson, Håkan A1 - Painter, Jodie N A1 - Patel, Alpa V A1 - Pedersen, Nancy L A1 - Perjakova, Natalia A1 - Peters, Annette A1 - Peters, Ulrike A1 - Pharoah, Paul D P A1 - Polasek, Ozren A1 - Porcu, Eleonora A1 - Psaty, Bruce M A1 - Rahman, Iffat A1 - Rennert, Gad A1 - Rennert, Hedy S A1 - Ridker, Paul M A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rossouw, Jacques A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Saloustros, Emmanouil A1 - Sandler, Dale P A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Sarnowski, Chloe A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schoemaker, Minouk J A1 - Schraut, Katharina E A1 - Scott, Christopher A1 - Shekari, Saleh A1 - Shrikhande, Amruta A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Spector, Tim D A1 - Spinelli, John J A1 - Stampfer, Meir A1 - Stöckl, Doris A1 - van Meurs, Joyce B J A1 - Strauch, Konstantin A1 - Styrkarsdottir, Unnur A1 - Swerdlow, Anthony J A1 - Tanaka, Toshiko A1 - Teras, Lauren R A1 - Teumer, Alexander A1 - Þorsteinsdottir, Unnur A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Troester, Melissa A A1 - Truong, Thérèse A1 - Tyrrell, Jessica A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Vachon, Celine M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wang, Qin A1 - Wareham, Nicholas J A1 - Weinberg, Clarice R A1 - Weir, David R A1 - Wilcox, Amber N A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wolk, Alicja A1 - Wood, Andrew R A1 - Zhao, Wei A1 - Zygmunt, Marek A1 - Chen, Zhengming A1 - Li, Liming A1 - Franke, Lude A1 - Burgess, Stephen A1 - Deelen, Patrick A1 - Pers, Tune H A1 - Grøndahl, Marie Louise A1 - Andersen, Claus Yding A1 - Pujol, Anna A1 - Lopez-Contreras, Andres J A1 - Daniel, Jeremy A A1 - Stefansson, Kari A1 - Chang-Claude, Jenny A1 - van der Schouw, Yvonne T A1 - Lunetta, Kathryn L A1 - Chasman, Daniel I A1 - Easton, Douglas F A1 - Visser, Jenny A A1 - Ozanne, Susan E A1 - Namekawa, Satoshi H A1 - Solc, Petr A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Hoffmann, Eva R A1 - Murray, Anna A1 - Roig, Ignasi A1 - Perry, John R B AB -

Reproductive 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.

VL - 596 IS - 7872 ER - TY - JOUR T1 - {Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci JF - Hum Mol Genet Y1 - 2021 A1 - Ahluwalia, T. S. A1 - Prins, B. P. A1 - Abdollahi, M. A1 - Armstrong, N. J. A1 - Aslibekyan, S. A1 - Bain, L. A1 - Jefferis, B. A1 - Baumert, J. A1 - Beekman, M. A1 - Ben-Shlomo, Y. A1 - Bis, J. C. A1 - Mitchell, B. D. A1 - de Geus, E. A1 - Delgado, G. E. A1 - Marek, D. A1 - Eriksson, J. A1 - Kajantie, E. A1 - Kanoni, S. A1 - Kemp, J. P. A1 - Lu, C. A1 - Marioni, R. E. A1 - McLachlan, S. A1 - Milaneschi, Y. A1 - Nolte, I. M. A1 - Petrelis, A. M. A1 - Porcu, E. A1 - Sabater-Lleal, M. A1 - Naderi, E. A1 - Seppälä, I. A1 - Shah, T. A1 - Singhal, G. A1 - Standl, M. A1 - Teumer, A. A1 - Thalamuthu, A. A1 - Thiering, E. A1 - Trompet, S. A1 - Ballantyne, C. M. A1 - Benjamin, E. J. A1 - Casas, J. P. A1 - Toben, C. A1 - Dedoussis, G. A1 - Deelen, J. A1 - Durda, P. A1 - Engmann, J. A1 - Feitosa, M. F. A1 - Grallert, H. A1 - Hammarstedt, A. A1 - Harris, S. E. A1 - Homuth, G. A1 - Hottenga, J. J. A1 - Jalkanen, S. A1 - Jamshidi, Y. A1 - Jawahar, M. C. A1 - Jess, T. A1 - Kivimaki, M. A1 - Kleber, M. E. A1 - Lahti, J. A1 - Liu, Y. A1 - Marques-Vidal, P. A1 - Mellström, D. A1 - Mooijaart, S. P. A1 - Müller-Nurasyid, M. A1 - Penninx, B. A1 - Revez, J. A. A1 - Rossing, P. A1 - Räikkönen, K. A1 - Sattar, N. A1 - Scharnagl, H. A1 - Sennblad, B. A1 - Silveira, A. A1 - Pourcain, B. S. A1 - Timpson, N. J. A1 - Trollor, J. A1 - van Dongen, J. A1 - van Heemst, D. A1 - Visvikis-Siest, S. A1 - Vollenweider, P. A1 - Völker, U. A1 - Waldenberger, M. A1 - Willemsen, G. A1 - Zabaneh, D. A1 - Morris, R. W. A1 - Arnett, D. K. A1 - Baune, B. T. A1 - Boomsma, D. I. A1 - Chang, Y. C. A1 - Deary, I. J. A1 - Deloukas, P. A1 - Eriksson, J. G. A1 - Evans, D. M. A1 - Ferreira, M. A. A1 - Gaunt, T. A1 - Gudnason, V. A1 - Hamsten, A. A1 - Heinrich, J. A1 - Hingorani, A. A1 - Humphries, S. E. A1 - Jukema, J. W. A1 - Koeing, W. A1 - Kumari, M. A1 - Kutalik, Z. A1 - Lawlor, D. A. A1 - Lehtimäki, T. A1 - März, W. A1 - Mather, K. A1 - Naitza, S. A1 - Nauck, M. A1 - Ohlsson, C. A1 - Price, J. F. A1 - Raitakari, O. A1 - Rice, K. A1 - Sachdev, P. S. A1 - Slagboom, E. A1 - Sørensen, T. I. A. A1 - Spector, T. A1 - Stacey, D. A1 - Stathopoulou, M. G. A1 - Tanaka, T. A1 - Wannamethee, S. G. A1 - Whincup, P. A1 - Rotter, J. I. A1 - Dehghan, A. A1 - Boerwinkle, E. A1 - Psaty, B. M. A1 - Snieder, H. A1 - Alizadeh, B. Z. AB - Interleukin-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. ER - TY - JOUR T1 - {Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women JF - Nat Commun Y1 - 2021 A1 - Jones, G. A1 - Trajanoska, K. A1 - Santanasto, A. J. A1 - Stringa, N. A1 - Kuo, C. L. A1 - Atkins, J. L. A1 - Lewis, J. R. A1 - Duong, T. A1 - Hong, S. A1 - Biggs, M. L. A1 - Luan, J. A1 - Sarnowski, C. A1 - Lunetta, K. L. A1 - Tanaka, T. A1 - Wojczynski, M. K. A1 - Cvejkus, R. A1 - Nethander, M. A1 - Ghasemi, S. A1 - Yang, J. A1 - Zillikens, M. C. A1 - Walter, S. A1 - Sicinski, K. A1 - Kague, E. A1 - Ackert-Bicknell, C. L. A1 - Arking, D. E. A1 - Windham, B. G. A1 - Boerwinkle, E. A1 - Grove, M. L. A1 - Graff, M. A1 - Spira, D. A1 - Demuth, I. A1 - Van der Velde, N. A1 - de Groot, L. C. P. G. M. A1 - Psaty, B. M. A1 - Odden, M. C. A1 - Fohner, A. E. A1 - Langenberg, C. A1 - Wareham, N. J. A1 - Bandinelli, S. A1 - van Schoor, N. M. A1 - Huisman, M. A1 - Tan, Q. A1 - Zmuda, J. A1 - Mellström, D. A1 - Karlsson, M. A1 - Bennett, D. A. A1 - Buchman, A. S. A1 - De Jager, P. L. A1 - Uitterlinden, A. G. A1 - Völker, U. A1 - Kocher, T. A1 - Teumer, A. A1 - Rodriguéz-Mañas, L. A1 - García, F. J. A1 - Carnicero, J. A. A1 - Herd, P. A1 - Bertram, L. A1 - Ohlsson, C. A1 - Murabito, J. M. A1 - Melzer, D. A1 - Kuchel, G. A. A1 - Ferrucci, L. A1 - Karasik, D. A1 - Rivadeneira, F. A1 - Kiel, D. P. A1 - Pilling, L. C. AB - Low 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. VL - 12 ER - TY - JOUR T1 - {The genomics of heart failure: design and rationale of the HERMES consortium JF - ESC Heart Fail Y1 - 2021 A1 - Lumbers, R. T. A1 - Shah, S. A1 - Lin, H. A1 - Czuba, T. A1 - Henry, A. A1 - Swerdlow, D. I. A1 - Malarstig, A. A1 - Andersson, C. A1 - Verweij, N. A1 - Holmes, M. V. A1 - Ärnlöv, J. A1 - Svensson, P. A1 - Hemingway, H. A1 - Sallah, N. A1 - Almgren, P. A1 - Aragam, K. G. A1 - Asselin, G. A1 - Backman, J. D. A1 - Biggs, M. L. A1 - Bloom, H. L. A1 - Boersma, E. A1 - Brandimarto, J. A1 - Brown, M. R. A1 - Brunner-La Rocca, H. P. A1 - Carey, D. J. A1 - Chaffin, M. D. A1 - Chasman, D. I. A1 - Chazara, O. A1 - Chen, X. A1 - Chen, X. A1 - Chung, J. H. A1 - Chutkow, W. A1 - Cleland, J. G. F. A1 - Cook, J. P. A1 - de Denus, S. A1 - Dehghan, A. A1 - Delgado, G. E. A1 - Denaxas, S. A1 - Doney, A. S. A1 - Dörr, M. A1 - Dudley, S. C. A1 - Engström, G. A1 - Esko, T. A1 - Fatemifar, G. A1 - Felix, S. B. A1 - Finan, C. A1 - Ford, I. A1 - Fougerousse, F. A1 - Fouodjio, R. A1 - Ghanbari, M. A1 - Ghasemi, S. A1 - Giedraitis, V. A1 - Giulianini, F. A1 - Gottdiener, J. S. A1 - Gross, S. A1 - Guðbjartsson, D. F. A1 - Gui, H. A1 - Gutmann, R. A1 - Haggerty, C. M. A1 - van der Harst, P. A1 - Hedman, Å. K. A1 - Helgadottir, A. A1 - Hillege, H. A1 - Hyde, C. L. A1 - Jacob, J. A1 - Jukema, J. W. A1 - Kamanu, F. A1 - Kardys, I. A1 - Kavousi, M. A1 - Khaw, K. T. A1 - Kleber, M. E. A1 - Køber, L. A1 - Koekemoer, A. A1 - Kraus, B. A1 - Kuchenbaecker, K. A1 - Langenberg, C. A1 - Lind, L. A1 - Lindgren, C. M. A1 - London, B. A1 - Lotta, L. A. A1 - Lovering, R. C. A1 - Luan, J. A1 - Magnusson, P. A1 - Mahajan, A. A1 - Mann, D. A1 - Margulies, K. B. A1 - Marston, N. A. A1 - März, W. A1 - McMurray, J. J. V. A1 - Melander, O. A1 - Melloni, G. A1 - Mordi, I. R. A1 - Morley, M. P. A1 - Morris, A. D. A1 - Morris, A. P. A1 - Morrison, A. C. A1 - Nagle, M. W. A1 - Nelson, C. P. A1 - Newton-Cheh, C. A1 - Niessner, A. A1 - Niiranen, T. A1 - Nowak, C. A1 - O'Donoghue, M. L. A1 - Owens, A. T. A1 - Palmer, C. N. A. A1 - Pare, G. A1 - Perola, M. A1 - Perreault, L. L. A1 - Portilla-Fernandez, E. A1 - Psaty, B. M. A1 - Rice, K. M. A1 - Ridker, P. M. A1 - Romaine, S. P. R. A1 - Roselli, C. A1 - Rotter, J. I. A1 - Ruff, C. T. A1 - Sabatine, M. S. A1 - Salo, P. A1 - Salomaa, V. A1 - van Setten, J. A1 - Shalaby, A. A. A1 - Smelser, D. T. A1 - Smith, N. L. A1 - Stefansson, K. A1 - Stender, S. A1 - Stott, D. J. A1 - Sveinbjornsson, G. A1 - Tammesoo, M. L. A1 - Tardif, J. C. A1 - Taylor, K. D. A1 - Teder-Laving, M. A1 - Teumer, A. A1 - Thorgeirsson, G. A1 - Thorsteinsdottir, U. A1 - Torp-Pedersen, C. A1 - Trompet, S. A1 - Tuckwell, D. A1 - Tyl, B. A1 - Uitterlinden, A. G. A1 - Vaura, F. A1 - Veluchamy, A. A1 - Visscher, P. M. A1 - Völker, U. A1 - Voors, A. A. A1 - Wang, X. A1 - Wareham, N. J. A1 - Weeke, P. E. A1 - Weiss, R. A1 - White, H. D. A1 - Wiggins, K. L. A1 - Xing, H. A1 - Yang, J. A1 - Yang, Y. A1 - Yerges-Armstrong, L. M. A1 - Yu, B. A1 - Zannad, F. A1 - Zhao, F. A1 - Wilk, J. B. A1 - Holm, H. A1 - Sattar, N. A1 - Lubitz, S. A. A1 - Lanfear, D. E. A1 - Shah, S. A1 - Dunn, M. E. A1 - Wells, Q. S. A1 - Asselbergs, F. W. A1 - Hingorani, A. D. A1 - Dubé, M. P. A1 - Samani, N. J. A1 - Lang, C. C. A1 - Cappola, T. P. A1 - Ellinor, P. T. A1 - Vasan, R. S. A1 - Smith, J. G. AB - The 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. ER - TY - JOUR T1 - Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation. JF - Circ Genom Precis Med Y1 - 2021 A1 - Yang, Yunju A1 - Bartz, Traci M A1 - Brown, Michael R A1 - Guo, Xiuqing A1 - Zilhão, Nuno R A1 - Trompet, Stella A1 - Weiss, Stefan A1 - Yao, Jie A1 - Brody, Jennifer A A1 - deFilippi, Christopher R A1 - Hoogeveen, Ron C A1 - Lin, Henry J A1 - Gudnason, Vilmundur A1 - Ballantyne, Christie M A1 - Dörr, Marcus A1 - Jukema, J Wouter A1 - Petersmann, Astrid A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Jun, Goo A1 - Yu, Bing AB -

BACKGROUND: 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.

VL - 14 IS - 6 ER - TY - JOUR T1 - Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program. JF - PLoS One Y1 - 2021 A1 - Sarnowski, Chloe A1 - Chen, Han A1 - Biggs, Mary L A1 - Wassertheil-Smoller, Sylvia A1 - Bressler, Jan A1 - Irvin, Marguerite R A1 - Ryan, Kathleen A A1 - Karasik, David A1 - Arnett, Donna K A1 - Cupples, L Adrienne A1 - Fardo, David W A1 - Gogarten, Stephanie M A1 - Heavner, Benjamin D A1 - Jain, Deepti A1 - Kang, Hyun Min A1 - Kooperberg, Charles A1 - Mainous, Arch G A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - O'Connell, Jeffrey R A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Smith, Albert V A1 - Vasan, Ramachandran S A1 - Windham, B Gwen A1 - Kiel, Douglas P A1 - Murabito, Joanne M A1 - Lunetta, Kathryn L AB -

Handgrip 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.

VL - 16 IS - 7 ER - TY - JOUR T1 - Individual non-esterified fatty acids and incident atrial fibrillation late in life. JF - Heart Y1 - 2021 A1 - Pellegrini, Cara N A1 - Bůzková, Petra A1 - Lichtenstein, Alice H A1 - Matthan, Nirupa R A1 - Ix, Joachim H A1 - Siscovick, David S A1 - Heckbert, Susan R A1 - Tracy, Russell P A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Kizer, Jorge R AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults. JF - J Am Heart Assoc Y1 - 2021 A1 - Lee, Yujin A1 - Nemet, Ina A1 - Wang, Zeneng A1 - Lai, Heidi T M A1 - de Oliveira Otto, Marcia C A1 - Lemaitre, Rozenn N A1 - Fretts, Amanda M A1 - Sotoodehnia, Nona A1 - Budoff, Matthew A1 - DiDonato, Joseph A A1 - McKnight, Barbara A1 - Tang, W H Wilson A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Hazen, Stanley L A1 - Mozaffarian, Dariush AB -

Background 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.

ER - TY - JOUR T1 - Meta-analyses identify DNA methylation associated with kidney function and damage. JF - Nat Commun Y1 - 2021 A1 - Schlosser, Pascal A1 - Tin, Adrienne A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Weihs, Antoine A1 - Yu, Zhi A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Chambers, John C A1 - Cole, Shelley A A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - de Klein, Niek A1 - Delgado, Graciela E A1 - Domingo-Relloso, Arce A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Evans, Kathryn L A1 - Floyd, James S A1 - Fornage, Myriam A1 - Franke, Lude A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kramer, Holly A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Liu, Yongmei A1 - Lloyd-Jones, Donald M A1 - Lohman, Kurt A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Navas-Acien, Ana A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Rosas, Sylvia E A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - Tellez-Plaza, Maria A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Verweij, Niek A1 - Walker, Rosie M A1 - Wielscher, Matthias A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Susztak, Katalin A1 - Köttgen, Anna A1 - Teumer, Alexander KW - Adult KW - Aged KW - CpG Islands KW - DNA Methylation KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Interferon Regulatory Factors KW - Kidney KW - Kidney Function Tests KW - LIM Domain Proteins KW - Male KW - Membrane Proteins KW - Middle Aged KW - Renal Insufficiency, Chronic KW - Transcription Factors AB -

Chronic 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.

VL - 12 IS - 1 ER - TY - JOUR T1 - Meta-analysis of epigenome-wide association studies of carotid intima-media thickness. JF - Eur J Epidemiol Y1 - 2021 A1 - Portilla-Fernández, Eliana A1 - Hwang, Shih-Jen A1 - Wilson, Rory A1 - Maddock, Jane A1 - Hill, W David A1 - Teumer, Alexander A1 - Mishra, Pashupati P A1 - Brody, Jennifer A A1 - Joehanes, Roby A1 - Ligthart, Symen A1 - Ghanbari, Mohsen A1 - Kavousi, Maryam A1 - Roks, Anton J M A1 - Danser, A H Jan A1 - Levy, Daniel A1 - Peters, Annette A1 - Ghasemi, Sahar A1 - Schminke, Ulf A1 - Dörr, Marcus A1 - Grabe, Hans J A1 - Lehtimäki, Terho A1 - Kähönen, Mika A1 - Hurme, Mikko A A1 - Bartz, Traci M A1 - Sotoodehnia, Nona A1 - Bis, Joshua C A1 - Thiery, Joachim A1 - Koenig, Wolfgang A1 - Ong, Ken K A1 - Bell, Jordana T A1 - Meisinger, Christine A1 - Wardlaw, Joanna M A1 - Starr, John M A1 - Seissler, Jochen A1 - Then, Cornelia A1 - Rathmann, Wolfgang A1 - Ikram, M Arfan A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Völzke, Henry A1 - Deary, Ian J A1 - Wong, Andrew A1 - Waldenberger, Melanie A1 - O'Donnell, Christopher J A1 - Dehghan, Abbas AB -

Common 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.

ER - TY - JOUR T1 - Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. JF - HGG Adv Y1 - 2021 A1 - Sun, Daokun A1 - Richard, Melissa A1 - Musani, Solomon K A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Schwander, Karen A1 - Chai, Jin Fang A1 - Guo, Xiuqing A1 - Kilpeläinen, Tuomas O A1 - Vojinovic, Dina A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Brown, Michael R A1 - Chitrala, Kumaraswamy A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Noordam, Raymond A1 - Smith, Albert V A1 - Harris, Sarah E A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - van der Most, Peter J A1 - Wang, Rujia A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Barac, Ana A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Chakravarti, Aravinda A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - Davigulus, Martha L A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Vries, Paul S A1 - Delaney, Joseph A C A1 - Roux, Ana V Diez A1 - Dörr, Marcus A1 - Faul, Jessica D A1 - Fretts, Amanda M A1 - Gallo, Linda C A1 - Grabe, Hans Jörgen A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Hartman, Catharina C A A1 - Heikkinen, Sami A1 - Ikram, M Arfan A1 - Isasi, Carmen A1 - Johnson, W Craig A1 - Jonas, Jost Bruno A1 - Kaplan, Robert C A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Levy, Daniel A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Luik, Annemarie I A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - O'Connell, Jeff R A1 - Palmas, Walter R A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Pulkki-Råback, Laura A1 - Raffel, Leslie J A1 - Reiner, Alex P A1 - Rice, Kenneth A1 - Robinson, Jennifer G A1 - Rosendaal, Frits R A1 - Schmidt, Carsten Oliver A1 - Schreiner, Pamela J A1 - Schwettmann, Lars A1 - Shikany, James M A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Waldenberger, Melanie A1 - Wee, Hwee-Lin A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Zeng, Donglin A1 - Zhao, Wei A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Deary, Ian J A1 - Gieger, Christian A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Snieder, Harold A1 - Wang, Ya-Xing A1 - Weir, David R A1 - Zheng, Wei A1 - Evans, Michele K A1 - Gauderman, W James A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Amin, Najaf A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Sim, Xueling A1 - Bierut, Laura A1 - Rotter, Jerome I A1 - Kardia, Sharon L R A1 - Franceschini, Nora A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Psychological 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.

VL - 2 IS - 1 ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. JF - Mol Psychiatry Y1 - 2021 A1 - Wang, Heming A1 - Noordam, Raymond A1 - Cade, Brian E A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Lee, Jiwon A1 - Sung, Yun Ju A1 - Bentley, Amy R A1 - Manning, Alisa K A1 - Aschard, Hugues A1 - Kilpeläinen, Tuomas O A1 - Ilkov, Marjan A1 - Brown, Michael R A1 - Horimoto, Andrea R A1 - Richard, Melissa A1 - Bartz, Traci M A1 - Vojinovic, Dina A1 - Lim, Elise A1 - Nierenberg, Jovia L A1 - Liu, Yongmei A1 - Chitrala, Kumaraswamynaidu A1 - Rankinen, Tuomo A1 - Musani, Solomon K A1 - Franceschini, Nora A1 - Rauramaa, Rainer A1 - Alver, Maris A1 - Zee, Phyllis C A1 - Harris, Sarah E A1 - van der Most, Peter J A1 - Nolte, Ilja M A1 - Munroe, Patricia B A1 - Palmer, Nicholette D A1 - Kuhnel, Brigitte A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Hall, Kelly A A1 - Lyytikäinen, Leo-Pekka A1 - O'Connell, Jeff A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - de Vries, Paul S A1 - Arking, Dan E A1 - Chen, Han A1 - Boerwinkle, Eric A1 - Krieger, Jose E A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Shikany, James M A1 - Rice, Kenneth A1 - Chen, Yii-Der Ida A1 - Gharib, Sina A A1 - Bis, Joshua C A1 - Luik, Annemarie I A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Amin, Najaf A1 - Xu, Hanfei A1 - Levy, Daniel A1 - He, Jiang A1 - Lohman, Kurt K A1 - Zonderman, Alan B A1 - Rice, Treva K A1 - Sims, Mario A1 - Wilson, Gregory A1 - Sofer, Tamar A1 - Rich, Stephen S A1 - Palmas, Walter A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Biermasz, Nienke R A1 - Mook-Kanamori, Dennis O A1 - Martin, Lisa W A1 - Barac, Ana A1 - Wallace, Robert B A1 - Gottlieb, Daniel J A1 - Komulainen, Pirjo A1 - Heikkinen, Sami A1 - Mägi, Reedik A1 - Milani, Lili A1 - Metspalu, Andres A1 - Starr, John M A1 - Milaneschi, Yuri A1 - Waken, R J A1 - Gao, Chuan A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Roenneberg, Till A1 - Völker, Uwe A1 - Dörr, Marcus A1 - Shu, Xiao-Ou A1 - Mukherjee, Sutapa A1 - Hillman, David R A1 - Kähönen, Mika A1 - Wagenknecht, Lynne E A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Zheng, Wei A1 - Palmer, Lyle J A1 - Lehtimäki, Terho A1 - Gudnason, Vilmundur A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Liu, Ching-Ti A1 - Kelly, Tanika N A1 - Evans, Michele K A1 - Bouchard, Claude A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Zhu, Xiaofeng A1 - Lakka, Timo A A1 - Esko, Tõnu A1 - North, Kari E A1 - Deary, Ian J A1 - Snieder, Harold A1 - Penninx, Brenda W J H A1 - Gauderman, W James A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - van Heemst, Diana AB -

Long 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.

ER - TY - JOUR T1 - {A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids JF - Nat Commun Y1 - 2021 A1 - Jhun, M. A. A1 - Mendelson, M. A1 - Wilson, R. A1 - Gondalia, R. A1 - Joehanes, R. A1 - Salfati, E. A1 - Zhao, X. A1 - Braun, K. V. E. A1 - Do, A. N. A1 - Hedman, Å. K. A1 - Zhang, T. A1 - Carnero-Montoro, E. A1 - Shen, J. A1 - Bartz, T. M. A1 - Brody, J. A. A1 - Montasser, M. E. A1 - O'Connell, J. R. A1 - Yao, C. A1 - Xia, R. A1 - Boerwinkle, E. A1 - Grove, M. A1 - Guan, W. A1 - Liliane, P. A1 - Singmann, P. A1 - Müller-Nurasyid, M. A1 - Meitinger, T. A1 - Gieger, C. A1 - Peters, A. A1 - Zhao, W. A1 - Ware, E. B. A1 - Smith, J. A. A1 - Dhana, K. A1 - van Meurs, J. A1 - Uitterlinden, A. A1 - Ikram, M. A. A1 - Ghanbari, M. A1 - Zhi, D. A1 - Gustafsson, S. A1 - Lind, L. A1 - Li, S. A1 - Sun, D. A1 - Spector, T. D. A1 - Chen, Y. I. A1 - Damcott, C. A1 - Shuldiner, A. R. A1 - Absher, D. M. A1 - Horvath, S. A1 - Tsao, P. S. A1 - Kardia, S. A1 - Psaty, B. M. A1 - Sotoodehnia, N. A1 - Bell, J. T. A1 - Ingelsson, E. A1 - Chen, W. A1 - Dehghan, A. A1 - Arnett, D. K. A1 - Waldenberger, M. A1 - Hou, L. A1 - Whitsel, E. A. A1 - Baccarelli, A. A1 - Levy, D. A1 - Fornage, M. A1 - Irvin, M. R. A1 - Assimes, T. L. AB - 10.1038/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. VL - 12 ER - TY - JOUR T1 - Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes. JF - Circ Genom Precis Med Y1 - 2021 A1 - Lu, Yingchang A1 - Dimitrov, Latchezar A1 - Chen, Shyh-Huei A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Lu, Lingyi A1 - Kavousi, Maryam A1 - Raffield, Laura M A1 - Smith, Albert V A1 - Wang, Lihua A1 - Weiss, Stefan A1 - Yao, Jie A1 - Zhu, Jiaxi A1 - Gudmundsson, Elias F A1 - Gudmundsdottir, Valborg A1 - Bos, Daniel A1 - Ghanbari, Mohsen A1 - Ikram, M Arfan A1 - Hwang, Shih-Jen A1 - Taylor, Kent D A1 - Budoff, Matthew J A1 - Gislason, Gauti K A1 - O'Donnell, Christopher J A1 - An, Ping A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Fu, Yi-Ping A1 - Guo, Xiuqing A1 - Heiss, Gerardo A1 - Kardia, Sharon L R A1 - Wilson, James G A1 - Langefeld, Carl D A1 - Schminke, Ulf A1 - Uitterlinden, André G A1 - Lange, Leslie A A1 - Peyser, Patricia A A1 - Gudnason, Vilmundur G A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Bowden, Donald W A1 - Ng, Maggie C Y AB -

BACKGROUND: 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.

VL - 14 IS - 4 ER - TY - JOUR T1 - is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. JF - Blood Cancer Discov Y1 - 2021 A1 - Beauchamp, Ellen M A1 - Leventhal, Matthew A1 - Bernard, Elsa A1 - Hoppe, Emma R A1 - Todisco, Gabriele A1 - Creignou, Maria A1 - Gallì, Anna A1 - Castellano, Cecilia A A1 - McConkey, Marie A1 - Tarun, Akansha A1 - Wong, Waihay A1 - Schenone, Monica A1 - Stanclift, Caroline A1 - Tanenbaum, Benjamin A1 - Malolepsza, Edyta A1 - Nilsson, Björn A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Miller, Mendy A1 - Niroula, Abhishek A1 - Dunford, Andrew A1 - Taylor-Weiner, Amaro A1 - Wood, Timothy A1 - Barbera, Alex A1 - Anand, Shankara A1 - Psaty, Bruce M A1 - Desai, Pinkal A1 - Cho, Michael H A1 - Johnson, Andrew D A1 - Loos, Ruth A1 - MacArthur, Daniel G A1 - Lek, Monkol A1 - Neuberg, Donna S A1 - Lage, Kasper A1 - Carr, Steven A A1 - Hellstrom-Lindberg, Eva A1 - Malcovati, Luca A1 - Papaemmanuil, Elli A1 - Stewart, Chip A1 - Getz, Gad A1 - Bradley, Robert K A1 - Jaiswal, Siddhartha A1 - Ebert, Benjamin L AB -

Clonal 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.

VL - 2 IS - 5 ER - TY - JOUR T1 - n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies JF - Diabetes Care Y1 - 2021 A1 - Qian, F. A1 - Ardisson Korat, A. V. A1 - Imamura, F. A1 - Marklund, M. A1 - Tintle, N. A1 - Virtanen, J. K. A1 - Zhou, X. A1 - Bassett, J. K. A1 - Lai, H. A1 - Hirakawa, Y. A1 - Chien, K. L. A1 - Wood, A. C. A1 - Lankinen, M. A1 - Murphy, R. A. A1 - Samieri, C. A1 - Pertiwi, K. A1 - de Mello, V. D. A1 - Guan, W. A1 - Forouhi, N. G. A1 - Wareham, N. A1 - Hu, I. C. F. B. A1 - Riserus, U. A1 - Lind, L. A1 - Harris, W. S. A1 - Shadyab, A. H. A1 - Robinson, J. G. A1 - Steffen, L. M. A1 - Hodge, A. A1 - Giles, G. G. A1 - Ninomiya, T. A1 - Uusitupa, M. A1 - Tuomilehto, J. A1 - m, J. A1 - Laakso, M. A1 - Siscovick, D. S. A1 - Helmer, C. A1 - Geleijnse, J. M. A1 - Wu, J. H. Y. A1 - Fretts, A. A1 - Lemaitre, R. N. A1 - Micha, R. A1 - Mozaffarian, D. A1 - Sun, Q. AB - -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. VL - 44 ER - TY - JOUR T1 - Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA). JF - BMC Cardiovasc Disord Y1 - 2021 A1 - Delaney, Joseph A C A1 - Olson, Nels C A1 - Sitlani, Colleen M A1 - Fohner, Alison E A1 - Huber, Sally A A1 - Landay, Alan L A1 - Heckbert, Susan R A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Feinstein, Matt A1 - Doyle, Margaret F AB -

BACKGROUND: 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.

VL - 21 IS - 1 ER - TY - JOUR T1 - Performance of the American Heart Association/American College of Cardiology Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Self-reported Physical Activity Levels. JF - JAMA Cardiol Y1 - 2021 A1 - Pandey, Ambarish A1 - Mehta, Anurag A1 - Paluch, Amanda A1 - Ning, Hongyan A1 - Carnethon, Mercedes R A1 - Allen, Norrina B A1 - Michos, Erin D A1 - Berry, Jarett D A1 - Lloyd-Jones, Donald M A1 - Wilkins, John T AB -

Importance: 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.

VL - 6 IS - 6 ER - TY - JOUR T1 - The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction. JF - Front Pharmacol Y1 - 2021 A1 - Trompet, Stella A1 - Postmus, Iris A1 - Warren, Helen R A1 - Noordam, Raymond A1 - Smit, Roelof A J A1 - Theusch, Elizabeth A1 - Li, Xiaohui A1 - Arsenault, Benoit A1 - Chasman, Daniel I A1 - Hitman, Graham A A1 - Munroe, Patricia B A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Caulfield, Mark J A1 - Krauss, Ron M A1 - Cupples, Adrienne L A1 - Jukema, Wouter J AB -

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.

VL - 12 ER - TY - JOUR T1 - Physical Function and Survival in Older Adults: A longitudinal study accounting for time-varying effects. JF - Arch Gerontol Geriatr Y1 - 2021 A1 - Karunananthan, Sathya A1 - Moodie, Erica E M A1 - Bergman, Howard A1 - Payette, Hélène A1 - Diehr, Paula H A1 - Wolfson, Christina AB -

PURPOSE 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.

VL - 96 ER - TY - JOUR T1 - {The power of genetic diversity in genome-wide association studies of lipids JF - Nature Y1 - 2021 A1 - Graham, S. E. A1 - Clarke, S. L. A1 - Wu, K. H. A1 - Kanoni, S. A1 - Zajac, G. J. M. A1 - Ramdas, S. A1 - Surakka, I. A1 - Ntalla, I. A1 - Vedantam, S. A1 - Winkler, T. W. A1 - Locke, A. E. A1 - Marouli, E. A1 - Hwang, M. Y. A1 - Han, S. A1 - Narita, A. A1 - Choudhury, A. A1 - Bentley, A. R. A1 - Ekoru, K. A1 - Verma, A. A1 - Trivedi, B. A1 - Martin, H. C. A1 - Hunt, K. A. A1 - Hui, Q. A1 - Klarin, D. A1 - Zhu, X. A1 - Thorleifsson, G. A1 - Helgadottir, A. A1 - Gudbjartsson, D. F. A1 - Holm, H. A1 - Olafsson, I. A1 - Akiyama, M. A1 - Sakaue, S. A1 - Terao, C. A1 - Kanai, M. A1 - Zhou, W. A1 - Brumpton, B. M. A1 - Rasheed, H. A1 - Ruotsalainen, S. E. A1 - Havulinna, A. S. A1 - Veturi, Y. A1 - Feng, Q. A1 - Rosenthal, E. A. A1 - Lingren, T. A1 - Pacheco, J. A. A1 - Pendergrass, S. A. A1 - Haessler, J. A1 - Giulianini, F. A1 - Bradford, Y. A1 - Miller, J. E. A1 - Campbell, A. A1 - Lin, K. A1 - Millwood, I. Y. A1 - Hindy, G. A1 - Rasheed, A. A1 - Faul, J. D. A1 - Zhao, W. A1 - Weir, D. R. A1 - Turman, C. A1 - Huang, H. A1 - Graff, M. A1 - Mahajan, A. A1 - Brown, M. R. A1 - Zhang, W. A1 - Yu, K. A1 - Schmidt, E. M. A1 - Pandit, A. A1 - Gustafsson, S. A1 - Yin, X. A1 - Luan, J. A1 - Zhao, J. H. A1 - Matsuda, F. A1 - Jang, H. M. A1 - Yoon, K. A1 - Medina-Gomez, C. A1 - Pitsillides, A. A1 - Hottenga, J. J. A1 - Willemsen, G. A1 - Wood, A. R. A1 - Ji, Y. A1 - Gao, Z. A1 - Haworth, S. A1 - Mitchell, R. E. A1 - Chai, J. F. A1 - Aadahl, M. A1 - Yao, J. A1 - Manichaikul, A. A1 - Warren, H. R. A1 - Ramirez, J. A1 - Bork-Jensen, J. A1 - Kårhus, L. L. A1 - Goel, A. A1 - Sabater-Lleal, M. A1 - Noordam, R. A1 - Sidore, C. A1 - Fiorillo, E. A1 - McDaid, A. F. A1 - Marques-Vidal, P. A1 - Wielscher, M. A1 - Trompet, S. A1 - Sattar, N. A1 - Møllehave, L. T. A1 - Thuesen, B. H. A1 - Munz, M. A1 - Zeng, L. A1 - Huang, J. A1 - Yang, B. A1 - Poveda, A. A1 - Kurbasic, A. A1 - Lamina, C. A1 - Forer, L. A1 - Scholz, M. A1 - Galesloot, T. E. A1 - Bradfield, J. P. A1 - Daw, E. W. A1 - Zmuda, J. M. A1 - Mitchell, J. S. A1 - Fuchsberger, C. A1 - Christensen, H. A1 - Brody, J. A. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - Preuss, M. A1 - Mangino, M. A1 - Christofidou, P. A1 - Verweij, N. A1 - Benjamins, J. W. A1 - Engmann, J. A1 - Kember, R. L. A1 - Slieker, R. C. A1 - Lo, K. S. A1 - Zilhao, N. R. A1 - Le, P. A1 - Kleber, M. E. A1 - Delgado, G. E. A1 - Huo, S. A1 - Ikeda, D. D. A1 - Iha, H. A1 - Yang, J. A1 - Liu, J. A1 - Leonard, H. L. A1 - Marten, J. A1 - Schmidt, B. A1 - Arendt, M. A1 - Smyth, L. J. A1 - Cañadas-Garre, M. A1 - Wang, C. A1 - Nakatochi, M. A1 - Wong, A. A1 - Hutri-Kähönen, N. A1 - Sim, X. A1 - Xia, R. A1 - Huerta-Chagoya, A. A1 - Fernandez-Lopez, J. C. A1 - Lyssenko, V. A1 - Ahmed, M. A1 - Jackson, A. U. A1 - Irvin, M. R. A1 - Oldmeadow, C. A1 - Kim, H. N. A1 - Ryu, S. A1 - Timmers, P. R. H. J. A1 - Arbeeva, L. 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A1 - Cuellar-Partida, G. A1 - Vestergaard, H. A1 - Hildalgo, B. A1 - Giannakopoulou, O. A1 - Cai, Q. A1 - Obura, M. O. A1 - van Setten, J. A1 - Li, X. A1 - Schwander, K. A1 - Terzikhan, N. A1 - Shin, J. H. A1 - Jackson, R. D. A1 - Reiner, A. P. A1 - Martin, L. W. A1 - Chen, Z. A1 - Li, L. A1 - Highland, H. M. A1 - Young, K. L. A1 - Kawaguchi, T. A1 - Thiery, J. A1 - Bis, J. C. A1 - Nadkarni, G. N. A1 - Launer, L. J. A1 - Li, H. A1 - Nalls, M. A. A1 - Raitakari, O. T. A1 - Ichihara, S. A1 - Wild, S. H. A1 - Nelson, C. P. A1 - Campbell, H. A1 - Jäger, S. A1 - Nabika, T. A1 - Al-Mulla, F. A1 - Niinikoski, H. A1 - Braund, P. S. A1 - Kolcic, I. A1 - Kovacs, P. A1 - Giardoglou, T. A1 - Katsuya, T. A1 - Bhatti, K. F. A1 - de Kleijn, D. A1 - de Borst, G. J. A1 - Kim, E. K. A1 - Adams, H. H. H. A1 - Ikram, M. A. A1 - Zhu, X. A1 - Asselbergs, F. W. A1 - Kraaijeveld, A. O. A1 - Beulens, J. W. J. A1 - Shu, X. O. A1 - Rallidis, L. S. A1 - Pedersen, O. A1 - Hansen, T. A1 - Mitchell, P. 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A1 - Pajukanta, P. A1 - Adair, L. S. A1 - Bechayda, S. A. A1 - de Silva, H. J. A1 - Wickremasinghe, A. R. A1 - Krauss, R. M. A1 - Wu, J. Y. A1 - Zheng, W. A1 - den Hollander, A. I. A1 - Bharadwaj, D. A1 - Correa, A. A1 - Wilson, J. G. A1 - Lind, L. A1 - Heng, C. K. A1 - Nelson, A. E. A1 - Golightly, Y. M. A1 - Wilson, J. F. A1 - Penninx, B. A1 - Kim, H. L. A1 - Attia, J. A1 - Scott, R. J. A1 - Rao, D. C. A1 - Arnett, D. K. A1 - Walker, M. A1 - Koistinen, H. A. A1 - Chandak, G. R. A1 - Yajnik, C. S. A1 - Mercader, J. M. A1 - Tusié-Luna, T. A1 - Aguilar-Salinas, C. A. A1 - Villalpando, C. G. A1 - Orozco, L. A1 - Fornage, M. A1 - Tai, E. S. A1 - van Dam, R. M. A1 - Lehtimäki, T. A1 - Chaturvedi, N. A1 - Yokota, M. A1 - Liu, J. A1 - Reilly, D. F. A1 - McKnight, A. J. A1 - Kee, F. A1 - Jöckel, K. H. A1 - McCarthy, M. I. A1 - Palmer, C. N. A. A1 - Vitart, V. A1 - Hayward, C. A1 - Simonsick, E. A1 - van Duijn, C. M. A1 - Lu, F. A1 - Qu, J. A1 - Hishigaki, H. A1 - Lin, X. A1 - März, W. A1 - Parra, E. J. A1 - Cruz, M. A1 - Gudnason, V. A1 - Tardif, J. C. A1 - Lettre, G. A1 - 't Hart, L. M. A1 - Elders, P. J. M. A1 - Damrauer, S. M. A1 - Kumari, M. A1 - Kivimaki, M. A1 - van der Harst, P. A1 - Spector, T. D. A1 - Loos, R. J. F. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Brandslund, I. A1 - Pramstaller, P. P. A1 - Christensen, K. A1 - Ripatti, S. A1 - Widén, E. A1 - Hakonarson, H. A1 - Grant, S. F. A. A1 - Kiemeney, L. A. L. M. A1 - de Graaf, J. A1 - Loeffler, M. A1 - Kronenberg, F. A1 - Gu, D. A1 - Erdmann, J. A1 - Schunkert, H. A1 - Franks, P. W. A1 - Linneberg, A. A1 - Jukema, J. W. A1 - Khera, A. V. A1 - Männikkö, M. A1 - Jarvelin, M. R. A1 - Kutalik, Z. A1 - Cucca, F. A1 - Mook-Kanamori, D. O. A1 - van Dijk, K. W. A1 - Watkins, H. A1 - Strachan, D. P. A1 - Grarup, N. A1 - Sever, P. A1 - Poulter, N. A1 - Rotter, J. I. A1 - Dantoft, T. M. A1 - Karpe, F. A1 - Neville, M. J. A1 - Timpson, N. J. A1 - Cheng, C. Y. A1 - Wong, T. Y. A1 - Khor, C. C. A1 - Sabanayagam, C. A1 - Peters, A. A1 - Gieger, C. A1 - Hattersley, A. T. A1 - Pedersen, N. L. A1 - Magnusson, P. K. E. A1 - Boomsma, D. I. A1 - de Geus, E. J. C. A1 - Cupples, L. A. A1 - van Meurs, J. B. J. A1 - Ghanbari, M. A1 - Gordon-Larsen, P. A1 - Huang, W. A1 - Kim, Y. J. A1 - Tabara, Y. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Zeggini, E. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Ingelsson, E. A1 - Abecasis, G. A1 - Chambers, J. C. A1 - Kooner, J. S. A1 - de Vries, P. S. A1 - Morrison, A. C. A1 - North, K. E. A1 - Daviglus, M. A1 - Kraft, P. A1 - Martin, N. G. A1 - Whitfield, J. B. A1 - Abbas, S. A1 - Saleheen, D. A1 - Walters, R. G. A1 - Holmes, M. V. A1 - Black, C. A1 - Smith, B. H. A1 - Justice, A. E. A1 - Baras, A. A1 - Buring, J. E. A1 - Ridker, P. M. A1 - Chasman, D. I. A1 - Kooperberg, C. A1 - Wei, W. Q. A1 - Jarvik, G. P. A1 - Namjou, B. A1 - Hayes, M. G. A1 - Ritchie, M. D. A1 - Jousilahti, P. A1 - Salomaa, V. A1 - Hveem, K. A1 - Åsvold, B. O. A1 - Kubo, M. A1 - Kamatani, Y. A1 - Okada, Y. A1 - Murakami, Y. A1 - Thorsteinsdottir, U. A1 - Stefansson, K. A1 - Ho, Y. L. A1 - Lynch, J. A. A1 - Rader, D. J. A1 - Tsao, P. S. A1 - Chang, K. M. A1 - Cho, K. A1 - O'Donnell, C. J. A1 - Gaziano, J. M. A1 - Wilson, P. A1 - Rotimi, C. N. A1 - Hazelhurst, S. A1 - Ramsay, M. A1 - Trembath, R. C. A1 - van Heel, D. A. A1 - Tamiya, G. A1 - Yamamoto, M. A1 - Kim, B. J. A1 - Mohlke, K. L. A1 - Frayling, T. M. A1 - Hirschhorn, J. N. A1 - Kathiresan, S. A1 - Boehnke, M. A1 - Natarajan, P. A1 - Peloso, G. M. A1 - Brown, C. D. A1 - Morris, A. P. A1 - Assimes, T. L. A1 - Deloukas, P. A1 - Sun, Y. V. A1 - Willer, C. J. AB - application of polygenic scores in clinical practice. VL - 600 ER - TY - JOUR T1 - Premature ventricular complexes and development of heart failure in a community-based population. JF - Heart Y1 - 2021 A1 - Limpitikul, Worawan B A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Soliman, Elsayed A1 - Nah, Gregory A1 - Fang, Christina A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Heckbert, Susan A1 - Stein, Phyllis K A1 - Gottdiener, John A1 - Hu, Xiao A1 - Hempfling, Ralf A1 - Marcus, Gregory M AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - {Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function JF - Sci Rep Y1 - 2021 A1 - Yang, T. A1 - Jackson, V. E. A1 - Smith, A. V. A1 - Chen, H. A1 - Bartz, T. M. A1 - Sitlani, C. M. A1 - Psaty, B. M. A1 - Gharib, S. A. A1 - O'Connor, G. T. A1 - Dupuis, J. A1 - Xu, J. A1 - Lohman, K. A1 - Liu, Y. A1 - Kritchevsky, S. B. A1 - Cassano, P. A. A1 - Flexeder, C. A1 - Gieger, C. A1 - Karrasch, S. A1 - Peters, A. A1 - Schulz, H. A1 - Harris, S. E. A1 - Starr, J. M. A1 - Deary, I. J. A1 - Manichaikul, A. A1 - Oelsner, E. C. A1 - Barr, R. G. A1 - Taylor, K. D. A1 - Rich, S. S. A1 - Bonten, T. N. A1 - Mook-Kanamori, D. O. A1 - Noordam, R. A1 - Li-Gao, R. A1 - Jarvelin, M. R. A1 - Wielscher, M. A1 - Terzikhan, N. A1 - Lahousse, L. A1 - Brusselle, G. A1 - Weiss, S. A1 - Ewert, R. A1 - Gläser, S. A1 - Homuth, G. A1 - Shrine, N. A1 - Hall, I. P. A1 - Tobin, M. A1 - London, S. J. A1 - Wei, P. A1 - Morrison, A. C. AB - . This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function. VL - 11 ER - TY - JOUR T1 - {Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis JF - Circ Genom Precis Med Y1 - 2021 A1 - Choi, S. H. A1 - Jurgens, S. J. A1 - Haggerty, C. M. A1 - Hall, A. W. A1 - Halford, J. L. A1 - Morrill, V. N. A1 - Weng, L. C. A1 - Lagerman, B. A1 - Mirshahi, T. A1 - Pettinger, M. A1 - Guo, X. A1 - Lin, H. J. A1 - Alonso, A. A1 - Soliman, E. Z. A1 - Kornej, J. A1 - Lin, H. A1 - Moscati, A. A1 - Nadkarni, G. N. A1 - Brody, J. A. A1 - Wiggins, K. L. A1 - Cade, B. E. A1 - Lee, J. A1 - Austin-Tse, C. A1 - Blackwell, T. A1 - Chaffin, M. D. A1 - Lee, C. J. A1 - Rehm, H. L. A1 - Roselli, C. A1 - Redline, S. A1 - Mitchell, B. D. A1 - Sotoodehnia, N. A1 - Psaty, B. M. A1 - Heckbert, S. R. A1 - Loos, R. J. F. A1 - Vasan, R. S. A1 - Benjamin, E. J. A1 - Correa, A. A1 - Boerwinkle, E. A1 - Arking, D. E. A1 - Rotter, J. I. A1 - Rich, S. S. A1 - Whitsel, E. A. A1 - Perez, M. A1 - Kooperberg, C. A1 - Fornwalt, B. K. A1 - Lunetta, K. L. A1 - Ellinor, P. T. A1 - Lubitz, S. A. AB - Alterations 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. VL - 14 ER - TY - JOUR T1 - Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. JF - Nature Y1 - 2021 A1 - Taliun, Daniel A1 - Harris, Daniel N A1 - Kessler, Michael D A1 - Carlson, Jedidiah A1 - Szpiech, Zachary A A1 - Torres, Raul A1 - Taliun, Sarah A Gagliano A1 - Corvelo, André A1 - Gogarten, Stephanie M A1 - Kang, Hyun Min A1 - Pitsillides, Achilleas N A1 - LeFaive, Jonathon A1 - Lee, Seung-Been A1 - Tian, Xiaowen A1 - Browning, Brian L A1 - Das, Sayantan A1 - Emde, Anne-Katrin A1 - Clarke, Wayne E A1 - Loesch, Douglas P A1 - Shetty, Amol C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Wong, Quenna A1 - Liu, Xiaoming A1 - Conomos, Matthew P A1 - Bobo, Dean M A1 - Aguet, Francois A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ardlie, Kristin G A1 - Arking, Dan E A1 - Aslibekyan, Stella A1 - Auer, Paul L A1 - Barnard, John A1 - Barr, R Graham A1 - Barwick, Lucas A1 - Becker, Lewis C A1 - Beer, Rebecca L A1 - Benjamin, Emelia J A1 - Bielak, Lawrence F A1 - Blangero, John A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Burchard, Esteban G A1 - Cade, Brian E A1 - Casella, James F A1 - Chalazan, Brandon A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Cho, Michael H A1 - Choi, Seung Hoan A1 - Chung, Mina K A1 - Clish, Clary B A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Custer, Brian A1 - Darbar, Dawood A1 - Daya, Michelle A1 - de Andrade, Mariza A1 - DeMeo, Dawn L A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Emery, Leslie S A1 - Eng, Celeste A1 - Fatkin, Diane A1 - Fingerlin, Tasha A1 - Forer, Lukas A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fuchsberger, Christian A1 - Fullerton, Stephanie M A1 - Germer, Soren A1 - Gladwin, Mark T A1 - Gottlieb, Daniel J A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - He, Jiang A1 - Heard-Costa, Nancy L A1 - Heckbert, Susan R A1 - Irvin, Marguerite R A1 - Johnsen, Jill M A1 - Johnson, Andrew D A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Kelly, Shannon A1 - Kenny, Eimear E A1 - Kiel, Douglas P A1 - Klemmer, Robert A1 - Konkle, Barbara A A1 - Kooperberg, Charles A1 - Köttgen, Anna A1 - Lange, Leslie A A1 - Lasky-Su, Jessica A1 - Levy, Daniel A1 - Lin, Xihong A1 - Lin, Keng-Han A1 - Liu, Chunyu A1 - Loos, Ruth J F A1 - Garman, Lori A1 - Gerszten, Robert A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Mak, Angel C Y A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mathias, Rasika A A1 - McManus, David D A1 - McGarvey, Stephen T A1 - Meigs, James B A1 - Meyers, Deborah A A1 - Mikulla, Julie L A1 - Minear, Mollie A A1 - Mitchell, Braxton D A1 - Mohanty, Sanghamitra A1 - Montasser, May E A1 - Montgomery, Courtney A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Natale, Andrea A1 - Natarajan, Pradeep A1 - Nelson, Sarah C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pankratz, Nathan A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Pleiness, Jacob A1 - Post, Wendy S A1 - Psaty, Bruce M A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Roden, Dan A1 - Rotter, Jerome I A1 - Ruczinski, Ingo A1 - Sarnowski, Chloe A1 - Schoenherr, Sebastian A1 - Schwartz, David A A1 - Seo, Jeong-Sun A1 - Seshadri, Sudha A1 - Sheehan, Vivien A A1 - Sheu, Wayne H A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stilp, Adrienne M A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn A1 - Thornton, Timothy A A1 - Tracy, Russell P A1 - Van Den Berg, David J A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Vrieze, Scott A1 - Weeks, Daniel E A1 - Weir, Bruce S A1 - Weiss, Scott T A1 - Weng, Lu-Chen A1 - Willer, Cristen J A1 - Zhang, Yingze A1 - Zhao, Xutong A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Boerwinkle, Eric A1 - Gabriel, Stacey A1 - Gibbs, Richard A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Silverman, Edwin K A1 - Qasba, Pankaj A1 - Gan, Weiniu A1 - Papanicolaou, George J A1 - Nickerson, Deborah A A1 - Browning, Sharon R A1 - Zody, Michael C A1 - Zöllner, Sebastian A1 - Wilson, James G A1 - Cupples, L Adrienne A1 - Laurie, Cathy C A1 - Jaquish, Cashell E A1 - Hernandez, Ryan D A1 - O'Connor, Timothy D A1 - Abecasis, Goncalo R AB -

The 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%.

VL - 590 IS - 7845 ER - TY - JOUR T1 - Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS). JF - Nutrients Y1 - 2021 A1 - Huang, Neil K A1 - Bůzková, Petra A1 - Matthan, Nirupa R A1 - Djoussé, Luc A1 - Kizer, Jorge R A1 - Mukamal, Kenneth J A1 - Polak, Joseph F A1 - Lichtenstein, Alice H KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Biomarkers KW - Brachial Artery KW - Carotid Artery, Common KW - Carotid Intima-Media Thickness KW - Dilatation KW - Fatty Acids, Monounsaturated KW - Fatty Acids, Nonesterified KW - Female KW - Humans KW - Linoleic Acid KW - Male KW - Regional Blood Flow KW - Risk Factors KW - Ultrasonography AB -

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.

VL - 13 IS - 9 ER - TY - JOUR T1 - {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability JF - Nat Commun Y1 - 2021 A1 - Lagou, V. A1 - M?gi, R. A1 - Hottenga, J. J. A1 - Grallert, H. A1 - Perry, J. R. B. A1 - Bouatia-Naji, N. A1 - Marullo, L. A1 - Rybin, D. A1 - Jansen, R. A1 - Min, J. L. A1 - Dimas, A. S. A1 - Ulrich, A. A1 - Zudina, L. A1 - G?din, J. R. A1 - Jiang, L. A1 - Faggian, A. A1 - Bonnefond, A. A1 - Fadista, J. A1 - Stathopoulou, M. G. A1 - Isaacs, A. A1 - Willems, S. M. A1 - Navarro, P. A1 - Tanaka, T. A1 - Jackson, A. U. A1 - Montasser, M. E. A1 - O'Connell, J. R. A1 - Bielak, L. F. A1 - Webster, R. J. A1 - Saxena, R. A1 - Stafford, J. M. A1 - Pourcain, B. S. A1 - Timpson, N. J. A1 - Salo, P. A1 - Shin, S. Y. A1 - Amin, N. A1 - Smith, A. V. A1 - Li, G. A1 - Verweij, N. A1 - Goel, A. A1 - Ford, I. A1 - Johnson, P. C. D. A1 - Johnson, T. A1 - Kapur, K. A1 - Thorleifsson, G. A1 - Strawbridge, R. J. A1 - Rasmussen-Torvik, L. J. A1 - Esko, T. A1 - Mihailov, E. A1 - Fall, T. A1 - Fraser, R. M. A1 - Mahajan, A. A1 - Kanoni, S. A1 - Giedraitis, V. A1 - Kleber, M. E. A1 - Silbernagel, G. A1 - Meyer, J. A1 - M?ller-Nurasyid, M. A1 - Ganna, A. A1 - Sarin, A. P. A1 - Yengo, L. A1 - Shungin, D. A1 - Luan, J. A1 - Horikoshi, M. A1 - An, P. A1 - Sanna, S. A1 - Boettcher, Y. A1 - Rayner, N. W. A1 - Nolte, I. M. A1 - Zemunik, T. A1 - Iperen, E. V. A1 - Kovacs, P. A1 - Hastie, N. D. A1 - Wild, S. H. A1 - McLachlan, S. A1 - Campbell, S. A1 - Polasek, O. A1 - Carlson, O. A1 - Egan, J. A1 - Kiess, W. A1 - Willemsen, G. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Dimitriou, M. A1 - Hicks, A. A. A1 - Rauramaa, R. A1 - Bandinelli, S. A1 - Thorand, B. A1 - Liu, Y. A1 - Miljkovic, I. A1 - Lind, L. A1 - Doney, A. A1 - Perola, M. A1 - Hingorani, A. A1 - Kivimaki, M. A1 - Kumari, M. A1 - Bennett, A. J. A1 - Groves, C. J. A1 - Herder, C. A1 - Koistinen, H. A. A1 - Kinnunen, L. A1 - Faire, U. A1 - Bakker, S. J. L. A1 - Uusitupa, M. A1 - Palmer, C. N. A. A1 - Jukema, J. W. A1 - Sattar, N. A1 - Pouta, A. A1 - Snieder, H. A1 - Boerwinkle, E. A1 - Pankow, J. S. A1 - Magnusson, P. K. A1 - Krus, U. A1 - Scapoli, C. A1 - de Geus, E. J. C. N. A1 - Bl?her, M. A1 - Wolffenbuttel, B. H. R. A1 - Province, M. A. A1 - Abecasis, G. R. A1 - Meigs, J. B. A1 - Hovingh, G. K. A1 - Lindstr?m, J. A1 - Wilson, J. F. A1 - Wright, A. F. A1 - Dedoussis, G. V. A1 - Bornstein, S. R. A1 - Schwarz, P. E. H. A1 - T?njes, A. A1 - Winkelmann, B. R. A1 - Boehm, B. O. A1 - M?rz, W. A1 - Metspalu, A. A1 - Price, J. F. A1 - Deloukas, P. A1 - K?rner, A. A1 - Lakka, T. A. A1 - Keinanen-Kiukaanniemi, S. M. A1 - Saaristo, T. E. A1 - Bergman, R. N. A1 - Tuomilehto, J. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - M?nnist?, S. A1 - Franks, P. W. A1 - Hayward, C. A1 - Vitart, V. A1 - Kaprio, J. A1 - Visvikis-Siest, S. A1 - Balkau, B. A1 - Altshuler, D. A1 - Rudan, I. A1 - Stumvoll, M. A1 - Campbell, H. A1 - van Duijn, C. M. A1 - Gieger, C. A1 - Illig, T. A1 - Ferrucci, L. A1 - Pedersen, N. L. A1 - Pramstaller, P. P. A1 - Boehnke, M. A1 - Frayling, T. M. A1 - Shuldiner, A. R. A1 - Peyser, P. A. A1 - Kardia, S. L. R. A1 - Palmer, L. J. A1 - Penninx, B. W. A1 - Meneton, P. A1 - Harris, T. B. A1 - Navis, G. A1 - Harst, P. V. A1 - Smith, G. D. A1 - Forouhi, N. G. A1 - Loos, R. J. F. A1 - Salomaa, V. A1 - Soranzo, N. A1 - Boomsma, D. I. A1 - Groop, L. A1 - Tuomi, T. A1 - Hofman, A. A1 - Munroe, P. B. A1 - Gudnason, V. A1 - Siscovick, D. S. A1 - Watkins, H. A1 - Lecoeur, C. A1 - Vollenweider, P. A1 - Franco-Cereceda, A. A1 - Eriksson, P. A1 - Jarvelin, M. R. A1 - Stefansson, K. A1 - Hamsten, A. A1 - Nicholson, G. A1 - Karpe, F. A1 - Dermitzakis, E. T. A1 - Lindgren, C. M. A1 - McCarthy, M. I. A1 - Froguel, P. A1 - Kaakinen, M. A. A1 - Lyssenko, V. A1 - Watanabe, R. M. A1 - Ingelsson, E. A1 - Florez, J. C. A1 - Dupuis, J. A1 - Barroso, I. A1 - Morris, A. P. A1 - Prokopenko, I. AB - Differences 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. VL - 12 ER - TY - JOUR T1 - {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability JF - Nat Commun Y1 - 2021 A1 - Lagou, V. A1 - Mägi, R. A1 - Hottenga, J. J. A1 - Grallert, H. A1 - Perry, J. R. B. A1 - Bouatia-Naji, N. A1 - Marullo, L. A1 - Rybin, D. A1 - Jansen, R. A1 - Min, J. L. A1 - Dimas, A. S. A1 - Ulrich, A. A1 - Zudina, L. A1 - Gådin, J. R. A1 - Jiang, L. A1 - Faggian, A. A1 - Bonnefond, A. A1 - Fadista, J. A1 - Stathopoulou, M. G. A1 - Isaacs, A. A1 - Willems, S. M. A1 - Navarro, P. A1 - Tanaka, T. A1 - Jackson, A. U. A1 - Montasser, M. E. A1 - O'Connell, J. R. A1 - Bielak, L. F. A1 - Webster, R. J. A1 - Saxena, R. A1 - Stafford, J. M. A1 - Pourcain, B. S. A1 - Timpson, N. J. A1 - Salo, P. A1 - Shin, S. Y. A1 - Amin, N. A1 - Smith, A. V. A1 - Li, G. A1 - Verweij, N. A1 - Goel, A. A1 - Ford, I. A1 - Johnson, P. C. D. A1 - Johnson, T. A1 - Kapur, K. A1 - Thorleifsson, G. A1 - Strawbridge, R. J. A1 - Rasmussen-Torvik, L. J. A1 - Esko, T. A1 - Mihailov, E. A1 - Fall, T. A1 - Fraser, R. M. A1 - Mahajan, A. A1 - Kanoni, S. A1 - Giedraitis, V. A1 - Kleber, M. E. A1 - Silbernagel, G. A1 - Meyer, J. A1 - Müller-Nurasyid, M. A1 - Ganna, A. A1 - Sarin, A. P. A1 - Yengo, L. A1 - Shungin, D. A1 - Luan, J. A1 - Horikoshi, M. A1 - An, P. A1 - Sanna, S. A1 - Boettcher, Y. A1 - Rayner, N. W. A1 - Nolte, I. M. A1 - Zemunik, T. A1 - Iperen, E. V. A1 - Kovacs, P. A1 - Hastie, N. D. A1 - Wild, S. H. A1 - McLachlan, S. A1 - Campbell, S. A1 - Polasek, O. A1 - Carlson, O. A1 - Egan, J. A1 - Kiess, W. A1 - Willemsen, G. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Dimitriou, M. A1 - Hicks, A. A. A1 - Rauramaa, R. A1 - Bandinelli, S. A1 - Thorand, B. A1 - Liu, Y. A1 - Miljkovic, I. A1 - Lind, L. A1 - Doney, A. A1 - Perola, M. A1 - Hingorani, A. A1 - Kivimaki, M. A1 - Kumari, M. A1 - Bennett, A. J. A1 - Groves, C. J. A1 - Herder, C. A1 - Koistinen, H. A. A1 - Kinnunen, L. A1 - Faire, U. A1 - Bakker, S. J. L. A1 - Uusitupa, M. A1 - Palmer, C. N. A. A1 - Jukema, J. W. A1 - Sattar, N. A1 - Pouta, A. A1 - Snieder, H. A1 - Boerwinkle, E. A1 - Pankow, J. S. A1 - Magnusson, P. K. A1 - Krus, U. A1 - Scapoli, C. A1 - de Geus, E. J. C. N. A1 - Blüher, M. A1 - Wolffenbuttel, B. H. R. A1 - Province, M. A. A1 - Abecasis, G. R. A1 - Meigs, J. B. A1 - Hovingh, G. K. A1 - Lindström, J. A1 - Wilson, J. F. A1 - Wright, A. F. A1 - Dedoussis, G. V. A1 - Bornstein, S. R. A1 - Schwarz, P. E. H. A1 - Tonjes, A. A1 - Winkelmann, B. R. A1 - Boehm, B. O. A1 - März, W. A1 - Metspalu, A. A1 - Price, J. F. A1 - Deloukas, P. A1 - Körner, A. A1 - Lakka, T. A. A1 - Keinanen-Kiukaanniemi, S. M. A1 - Saaristo, T. E. A1 - Bergman, R. N. A1 - Tuomilehto, J. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Männistö, S. A1 - Franks, P. W. A1 - Hayward, C. A1 - Vitart, V. A1 - Kaprio, J. A1 - Visvikis-Siest, S. A1 - Balkau, B. A1 - Altshuler, D. A1 - Rudan, I. A1 - Stumvoll, M. A1 - Campbell, H. A1 - van Duijn, C. M. A1 - Gieger, C. A1 - Illig, T. A1 - Ferrucci, L. A1 - Pedersen, N. L. A1 - Pramstaller, P. P. A1 - Boehnke, M. A1 - Frayling, T. M. A1 - Shuldiner, A. R. A1 - Peyser, P. A. A1 - Kardia, S. L. R. A1 - Palmer, L. J. A1 - Penninx, B. W. A1 - Meneton, P. A1 - Harris, T. B. A1 - Navis, G. A1 - Harst, P. V. A1 - Smith, G. D. A1 - Forouhi, N. G. A1 - Loos, R. J. F. A1 - Salomaa, V. A1 - Soranzo, N. A1 - Boomsma, D. I. A1 - Groop, L. A1 - Tuomi, T. A1 - Hofman, A. A1 - Munroe, P. B. A1 - Gudnason, V. A1 - Siscovick, D. S. A1 - Watkins, H. A1 - Lecoeur, C. A1 - Vollenweider, P. A1 - Franco-Cereceda, A. A1 - Eriksson, P. A1 - Jarvelin, M. R. A1 - Stefansson, K. A1 - Hamsten, A. A1 - Nicholson, G. A1 - Karpe, F. A1 - Dermitzakis, E. T. A1 - Lindgren, C. M. A1 - McCarthy, M. I. A1 - Froguel, P. A1 - Kaakinen, M. A. A1 - Lyssenko, V. A1 - Watanabe, R. M. A1 - Ingelsson, E. A1 - Florez, J. C. A1 - Dupuis, J. A1 - Barroso, I. A1 - Morris, A. P. A1 - Prokopenko, I. AB - Differences 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. VL - 12 ER - TY - JOUR T1 - Silent Myocardial Infarction and Subsequent Ischemic Stroke in the Cardiovascular Health Study. JF - Neurology Y1 - 2021 A1 - Merkler, Alexander E A1 - Bartz, Traci M A1 - Kamel, Hooman A1 - Soliman, Elsayed Z A1 - Howard, Virginia A1 - Psaty, Bruce M A1 - Okin, Peter M A1 - Safford, Monika M A1 - Elkind, Mitchell S V A1 - Longstreth, W T AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - Sugar-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. JF - Circ Genom Precis Med Y1 - 2021 A1 - Haslam, Danielle E A1 - Peloso, Gina M A1 - Guirette, Melanie A1 - Imamura, Fumiaki A1 - Bartz, Traci M A1 - Pitsillides, Achilleas N A1 - Wang, Carol A A1 - Li-Gao, Ruifang A1 - Westra, Jason M A1 - Pitkänen, Niina A1 - Young, Kristin L A1 - Graff, Mariaelisa A1 - Wood, Alexis C A1 - Braun, Kim V E A1 - Luan, Jian'an A1 - Kähönen, Mika A1 - Kiefte-de Jong, Jessica C A1 - Ghanbari, Mohsen A1 - Tintle, Nathan A1 - Lemaitre, Rozenn N A1 - Mook-Kanamori, Dennis O A1 - North, Kari A1 - Helminen, Mika A1 - Mossavar-Rahmani, Yasmin A1 - Snetselaar, Linda A1 - Martin, Lisa W A1 - Viikari, Jorma S A1 - Oddy, Wendy H A1 - Pennell, Craig E A1 - Rosendall, Frits R A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Mozaffarian, Dariush A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Livingston, Kara A A1 - Voortman, Trudy A1 - Forouhi, Nita G A1 - Wareham, Nick J A1 - de Mutsert, Renée A1 - Rich, Steven S A1 - Manson, JoAnn E A1 - Mora, Samia A1 - Ridker, Paul M A1 - Merino, Jordi A1 - Meigs, James B A1 - Dashti, Hassan S A1 - Chasman, Daniel I A1 - Lichtenstein, Alice H A1 - Smith, Caren E A1 - Dupuis, Josée A1 - Herman, Mark A A1 - McKeown, Nicola M AB -

BACKGROUND: 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.

VL - 14 IS - 4 ER - TY - JOUR T1 - Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. JF - J Am Coll Cardiol Y1 - 2021 A1 - Yu, Bing A1 - Roberts, Mary B A1 - Raffield, Laura M A1 - Zekavat, Seyedeh Maryam A1 - Nguyen, Ngoc Quynh H A1 - Biggs, Mary L A1 - Brown, Michael R A1 - Griffin, Gabriel A1 - Desai, Pinkal A1 - Correa, Adolfo A1 - Morrison, Alanna C A1 - Shah, Amil M A1 - Niroula, Abhishek A1 - Uddin, Md Mesbah A1 - Honigberg, Michael C A1 - Ebert, Benjamin L A1 - Psaty, Bruce M A1 - Whitsel, Eric A A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Bick, Alexander G A1 - Ballantyne, Christie M A1 - Reiner, Alex P A1 - Natarajan, Pradeep A1 - Eaton, Charles B KW - Aged KW - Clonal Hematopoiesis KW - Correlation of Data KW - Demography KW - DNA-Binding Proteins KW - Female KW - Heart Failure KW - Humans KW - Janus Kinase 2 KW - Male KW - Middle Aged KW - Mutation KW - Proportional Hazards Models KW - Proto-Oncogene Proteins KW - Repressor Proteins KW - Risk Factors KW - Stroke Volume KW - Ventricular Dysfunction, Left KW - Whole Exome Sequencing AB -

BACKGROUND: 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.

VL - 78 IS - 1 ER - TY - JOUR T1 - A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. JF - Am J Epidemiol Y1 - 2021 A1 - Stilp, Adrienne M A1 - Emery, Leslie S A1 - Broome, Jai G A1 - Buth, Erin J A1 - Khan, Alyna T A1 - Laurie, Cecelia A A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Chen, Dongquan A1 - D'Augustine, Catherine M A1 - Heard-Costa, Nancy L A1 - Hohensee, Chancellor R A1 - Johnson, William Craig A1 - Juarez, Lucia D A1 - Liu, Jingmin A1 - Mutalik, Karen M A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - de Vries, Paul S A1 - Kelly, Tanika N A1 - Kooperberg, Charles A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Reiner, Alex P A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Barnes, Kathleen C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Chen, Ming-Huei A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - de Andrade, Mariza A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Gan, Weiniu A1 - Ganesh, Santhi K A1 - Graffelman, Jan A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hawley, Nicola L A1 - Hsu, Wan-Ling A1 - Jackson, Rebecca D A1 - Jaquish, Cashell E A1 - Johnson, Andrew D A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Lee, Jiwon A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - North, Kari E A1 - Nouraie, Seyed Mehdi A1 - Oelsner, Elizabeth C A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Weiss, Scott T A1 - Wilson, Carla G A1 - Yanek, Lisa R A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Laurie, Cathy C AB -

Genotype-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.

ER - TY - JOUR T1 - {The trans-ancestral genomic architecture of glycemic traits JF - Nat Genet Y1 - 2021 A1 - Chen, J. A1 - Spracklen, C. N. A1 - Marenne, G. A1 - Varshney, A. A1 - Corbin, L. J. A1 - Luan, J. A1 - Willems, S. M. A1 - Wu, Y. A1 - Zhang, X. A1 - Horikoshi, M. A1 - Boutin, T. S. A1 - Mägi, R. A1 - Waage, J. A1 - Li-Gao, R. A1 - Chan, K. H. K. A1 - Yao, J. A1 - Anasanti, M. D. A1 - Chu, A. Y. A1 - Claringbould, A. A1 - Heikkinen, J. A1 - Hong, J. A1 - Hottenga, J. J. A1 - Huo, S. A1 - Kaakinen, M. A. A1 - Louie, T. A1 - März, W. A1 - Moreno-Macias, H. A1 - Ndungu, A. A1 - Nelson, S. C. A1 - Nolte, I. M. A1 - North, K. E. A1 - Raulerson, C. K. A1 - Ray, D. A1 - Rohde, R. A1 - Rybin, D. A1 - Schurmann, C. A1 - Sim, X. A1 - Southam, L. A1 - Stewart, I. D. A1 - Wang, C. A. A1 - Wang, Y. A1 - Wu, P. A1 - Zhang, W. A1 - Ahluwalia, T. S. A1 - Appel, E. V. R. A1 - Bielak, L. F. A1 - Brody, J. A. A1 - Burtt, N. P. A1 - Cabrera, C. P. A1 - Cade, B. E. A1 - Chai, J. F. A1 - Chai, X. A1 - Chang, L. C. A1 - Chen, C. H. A1 - Chen, B. H. A1 - Chitrala, K. N. A1 - Chiu, Y. F. A1 - de Haan, H. G. A1 - Delgado, G. E. A1 - Demirkan, A. A1 - Duan, Q. A1 - Engmann, J. A1 - Fatumo, S. A. A1 - Gayán, J. A1 - Giulianini, F. A1 - Gong, J. H. A1 - Gustafsson, S. A1 - Hai, Y. A1 - Hartwig, F. P. A1 - He, J. A1 - Heianza, Y. A1 - Huang, T. A1 - Huerta-Chagoya, A. A1 - Hwang, M. Y. A1 - Jensen, R. A. A1 - Kawaguchi, T. A1 - Kentistou, K. A. A1 - Kim, Y. J. A1 - Kleber, M. E. A1 - Kooner, I. K. A1 - Lai, S. A1 - Lange, L. A. A1 - Langefeld, C. D. A1 - Lauzon, M. A1 - Li, M. A1 - Ligthart, S. A1 - Liu, J. A1 - Loh, M. A1 - Long, J. A1 - Lyssenko, V. A1 - Mangino, M. A1 - Marzi, C. A1 - Montasser, M. E. A1 - Nag, A. A1 - Nakatochi, M. A1 - Noce, D. A1 - Noordam, R. A1 - Pistis, G. A1 - Preuss, M. A1 - Raffield, L. A1 - Rasmussen-Torvik, L. J. A1 - Rich, S. S. A1 - Robertson, N. R. A1 - Rueedi, R. A1 - Ryan, K. A1 - Sanna, S. A1 - Saxena, R. A1 - Schraut, K. E. A1 - Sennblad, B. A1 - Setoh, K. A1 - Smith, A. V. A1 - Sparsø, T. A1 - Strawbridge, R. J. A1 - Takeuchi, F. A1 - Tan, J. A1 - Trompet, S. A1 - van den Akker, E. A1 - van der Most, P. J. A1 - Verweij, N. A1 - Vogel, M. A1 - Wang, H. A1 - Wang, C. A1 - Wang, N. A1 - Warren, H. R. A1 - Wen, W. A1 - Wilsgaard, T. A1 - Wong, A. A1 - Wood, A. R. A1 - Xie, T. A1 - Zafarmand, M. H. A1 - Zhao, J. H. A1 - Zhao, W. A1 - Amin, N. A1 - Arzumanyan, Z. A1 - Astrup, A. A1 - Bakker, S. J. L. A1 - Baldassarre, D. A1 - Beekman, M. A1 - Bergman, R. N. A1 - Bertoni, A. A1 - Blüher, M. A1 - Bonnycastle, L. L. A1 - Bornstein, S. R. A1 - Bowden, D. W. A1 - Cai, Q. A1 - Campbell, A. A1 - Campbell, H. A1 - Chang, Y. C. A1 - de Geus, E. J. C. A1 - Dehghan, A. A1 - Du, S. A1 - Eiriksdottir, G. A1 - Farmaki, A. E. A1 - Frånberg, M. A1 - Fuchsberger, C. A1 - Gao, Y. A1 - Gjesing, A. P. A1 - Goel, A. A1 - Han, S. A1 - Hartman, C. A. A1 - Herder, C. A1 - Hicks, A. A. A1 - Hsieh, C. H. A1 - Hsueh, W. A. A1 - Ichihara, S. A1 - Igase, M. A1 - Ikram, M. A. A1 - Johnson, W. C. A1 - Jørgensen, M. E. A1 - Joshi, P. K. A1 - Kalyani, R. R. A1 - Kandeel, F. R. A1 - Katsuya, T. A1 - Khor, C. C. A1 - Kiess, W. A1 - Kolcic, I. A1 - Kuulasmaa, T. A1 - Kuusisto, J. A1 - Läll, K. A1 - Lam, K. A1 - Lawlor, D. A. A1 - Lee, N. R. A1 - Lemaitre, R. N. A1 - Li, H. A1 - Lin, S. Y. A1 - Lindström, J. A1 - Linneberg, A. A1 - Liu, J. A1 - Lorenzo, C. A1 - Matsubara, T. A1 - Matsuda, F. A1 - Mingrone, G. A1 - Mooijaart, S. A1 - Moon, S. A1 - Nabika, T. A1 - Nadkarni, G. N. A1 - Nadler, J. L. A1 - Nelis, M. A1 - Neville, M. J. A1 - Norris, J. M. A1 - Ohyagi, Y. A1 - Peters, A. A1 - Peyser, P. A. A1 - Polasek, O. A1 - Qi, Q. A1 - Raven, D. A1 - Reilly, D. F. A1 - Reiner, A. A1 - Rivideneira, F. A1 - Roll, K. A1 - Rudan, I. A1 - Sabanayagam, C. A1 - Sandow, K. A1 - Sattar, N. A1 - Schürmann, A. A1 - Shi, J. A1 - Stringham, H. M. A1 - Taylor, K. D. A1 - Teslovich, T. M. A1 - Thuesen, B. A1 - Timmers, P. R. H. J. A1 - Tremoli, E. A1 - Tsai, M. Y. A1 - Uitterlinden, A. A1 - van Dam, R. M. A1 - van Heemst, D. A1 - van Hylckama Vlieg, A. A1 - Van Vliet-Ostaptchouk, J. V. A1 - Vangipurapu, J. A1 - Vestergaard, H. A1 - Wang, T. A1 - Willems van Dijk, K. A1 - Zemunik, T. A1 - Abecasis, G. R. A1 - Adair, L. S. A1 - Aguilar-Salinas, C. A. A1 - Alarcón-Riquelme, M. E. A1 - An, P. A1 - Aviles-Santa, L. A1 - Becker, D. M. A1 - Beilin, L. J. A1 - Bergmann, S. A1 - Bisgaard, H. A1 - Black, C. A1 - Boehnke, M. A1 - Boerwinkle, E. A1 - Böhm, B. O. A1 - Bønnelykke, K. A1 - Boomsma, D. I. A1 - Bottinger, E. P. A1 - Buchanan, T. A. A1 - Canouil, M. A1 - Caulfield, M. J. A1 - Chambers, J. C. A1 - Chasman, D. I. A1 - Chen, Y. I. A1 - Cheng, C. Y. A1 - Collins, F. S. A1 - Correa, A. A1 - Cucca, F. A1 - de Silva, H. J. A1 - Dedoussis, G. A1 - Elmståhl, S. A1 - Evans, M. K. A1 - Ferrannini, E. A1 - Ferrucci, L. A1 - Florez, J. C. A1 - Franks, P. W. A1 - Frayling, T. M. A1 - Froguel, P. A1 - Gigante, B. A1 - Goodarzi, M. O. A1 - Gordon-Larsen, P. A1 - Grallert, H. A1 - Grarup, N. A1 - Grimsgaard, S. A1 - Groop, L. A1 - Gudnason, V. A1 - Guo, X. A1 - Hamsten, A. A1 - Hansen, T. A1 - Hayward, C. A1 - Heckbert, S. R. A1 - Horta, B. L. A1 - Huang, W. A1 - Ingelsson, E. A1 - James, P. S. A1 - Jarvelin, M. R. A1 - Jonas, J. B. A1 - Jukema, J. W. A1 - Kaleebu, P. A1 - Kaplan, R. A1 - Kardia, S. L. R. A1 - Kato, N. A1 - Keinanen-Kiukaanniemi, S. M. A1 - Kim, B. J. A1 - Kivimaki, M. A1 - Koistinen, H. A. A1 - Kooner, J. S. A1 - Körner, A. A1 - Kovacs, P. A1 - Kuh, D. A1 - Kumari, M. A1 - Kutalik, Z. A1 - Laakso, M. A1 - Lakka, T. A. A1 - Launer, L. J. A1 - Leander, K. A1 - Li, H. A1 - Lin, X. A1 - Lind, L. A1 - Lindgren, C. A1 - Liu, S. A1 - Loos, R. J. F. A1 - Magnusson, P. K. E. A1 - Mahajan, A. A1 - Metspalu, A. A1 - Mook-Kanamori, D. O. A1 - Mori, T. A. A1 - Munroe, P. B. A1 - Njølstad, I. A1 - O'Connell, J. R. A1 - Oldehinkel, A. J. A1 - Ong, K. K. A1 - Padmanabhan, S. A1 - Palmer, C. N. A. A1 - Palmer, N. D. A1 - Pedersen, O. A1 - Pennell, C. E. A1 - Porteous, D. J. A1 - Pramstaller, P. P. A1 - Province, M. A. A1 - Psaty, B. M. A1 - Qi, L. A1 - Raffel, L. J. A1 - Rauramaa, R. A1 - Redline, S. A1 - Ridker, P. M. A1 - Rosendaal, F. R. A1 - Saaristo, T. E. A1 - Sandhu, M. A1 - Saramies, J. A1 - Schneiderman, N. A1 - Schwarz, P. A1 - Scott, L. J. A1 - Selvin, E. A1 - Sever, P. A1 - Shu, X. O. A1 - Slagboom, P. E. A1 - Small, K. S. A1 - Smith, B. H. A1 - Snieder, H. A1 - Sofer, T. A1 - Sørensen, T. I. A. A1 - Spector, T. D. A1 - Stanton, A. A1 - Steves, C. J. A1 - Stumvoll, M. A1 - Sun, L. A1 - Tabara, Y. A1 - Tai, E. S. A1 - Timpson, N. J. A1 - Tonjes, A. A1 - Tuomilehto, J. A1 - Tusie, T. A1 - Uusitupa, M. A1 - van der Harst, P. A1 - van Duijn, C. A1 - Vitart, V. A1 - Vollenweider, P. A1 - Vrijkotte, T. G. M. A1 - Wagenknecht, L. E. A1 - Walker, M. A1 - Wang, Y. X. A1 - Wareham, N. J. A1 - Watanabe, R. M. A1 - Watkins, H. A1 - Wei, W. B. A1 - Wickremasinghe, A. R. A1 - Willemsen, G. A1 - Wilson, J. F. A1 - Wong, T. Y. A1 - Wu, J. Y. A1 - Xiang, A. H. A1 - Yanek, L. R. A1 - Yengo, L. A1 - Yokota, M. A1 - Zeggini, E. A1 - Zheng, W. A1 - Zonderman, A. B. A1 - Rotter, J. I. A1 - Gloyn, A. L. A1 - McCarthy, M. I. A1 - Dupuis, J. A1 - Meigs, J. B. A1 - Scott, R. A. A1 - Prokopenko, I. A1 - Leong, A. A1 - Liu, C. T. A1 - Parker, S. C. J. A1 - Mohlke, K. L. A1 - Langenberg, C. A1 - Wheeler, E. A1 - Morris, A. P. A1 - Barroso, I. A1 - de Haan, H. G. A1 - van den Akker, E. A1 - van der Most, P. J. A1 - de Geus, E. J. C. A1 - van Dam, R. M. A1 - van Heemst, D. A1 - van Hylckama Vlieg, A. A1 - van Willems van Dijk, K. A1 - de Silva, H. J. A1 - van der Harst, P. A1 - van Duijn, C. AB - 10.1038/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. VL - 53 ER - TY - JOUR T1 - What 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. JF - J Gerontol A Biol Sci Med Sci Y1 - 2021 A1 - Cawthon, Peggy M A1 - Patel, Sheena M A1 - Kritchevsky, Stephen B A1 - Newman, Anne B A1 - Santanasto, Adam A1 - Kiel, Douglas P A1 - Travison, Thomas G A1 - Lane, Nancy A1 - Cummings, Steven R A1 - Orwoll, Eric S A1 - Duchowny, Kate A A1 - Kwok, Timothy A1 - Hirani, Vasant A1 - Schousboe, John A1 - Karlsson, Magnus K A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Ljunggren, Osten A1 - Xue, Qian-Li A1 - Shardell, Michelle A1 - Jordan, Joanne M A1 - Pencina, Karol M A1 - Fielding, Roger A A1 - Magaziner, Jay A1 - Correa-de-Araujo, Rosaly A1 - Bhasin, Shalender A1 - Manini, Todd M KW - Aged KW - Female KW - Gait KW - Humans KW - Independent Living KW - Male KW - Mobility Limitation KW - Sarcopenia KW - Walking KW - Walking Speed AB -

BACKGROUND: 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.

VL - 76 IS - 10 ER - TY - JOUR T1 - Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. JF - EBioMedicine Y1 - 2021 A1 - Lin, Bridget M A1 - Grinde, Kelsey E A1 - Brody, Jennifer A A1 - Breeze, Charles E A1 - Raffield, Laura M A1 - Mychaleckyj, Josyf C A1 - Thornton, Timothy A A1 - Perry, James A A1 - Baier, Leslie J A1 - de Las Fuentes, Lisa A1 - Guo, Xiuqing A1 - Heavner, Benjamin D A1 - Hanson, Robert L A1 - Hung, Yi-Jen A1 - Qian, Huijun A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Irvin, Margaret R A1 - Jain, Deepti A1 - Kelly, Tanika N A1 - Kobes, Sayuko A1 - Lange, Leslie A1 - Lash, James P A1 - Li, Yun A1 - Liu, Xiaoming A1 - Mi, Xuenan A1 - Musani, Solomon K A1 - Papanicolaou, George J A1 - Parsa, Afshin A1 - Reiner, Alex P A1 - Salimi, Shabnam A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tin, Adrienne A1 - Vaidya, Dhananjay A1 - Wallace, Robert B A1 - Yamamoto, Kenichi A1 - Sakaue, Saori A1 - Matsuda, Koichi A1 - Kamatani, Yoichiro A1 - Momozawa, Yukihide A1 - Yanek, Lisa R A1 - Young, Betsi A A1 - Zhao, Wei A1 - Okada, Yukinori A1 - Abecasis, Gonzalo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Cai, Jianwen A1 - Yii-Der Chen, Ida A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - He, Jiang A1 - Kardia, Sharon Lr A1 - Kooperberg, Charles A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Nickerson, Deborah A A1 - Turner, Steve T A1 - Vasan, Ramachandran S A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Kramer, Holly J A1 - Köttgen, Anna A1 - Rich, Stephen S A1 - Lin, Dan-Yu A1 - Browning, Sharon R A1 - Franceschini, Nora AB -

BACKGROUND: 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.

VL - 63 ER - TY - JOUR T1 - Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative. JF - Hum Mol Genet Y1 - 2021 A1 - Little, Amarise A1 - Hu, Yao A1 - Sun, Quan A1 - Jain, Deepti A1 - Broome, Jai A1 - Chen, Ming-Huei A1 - Thibord, Florian A1 - McHugh, Caitlin A1 - Surendran, Praveen A1 - Blackwell, Thomas W A1 - Brody, Jennifer A A1 - Bhan, Arunoday A1 - Chami, Nathalie A1 - Vries, Paul S A1 - Ekunwe, Lynette A1 - Heard-Costa, Nancy A1 - Hobbs, Brian D A1 - Manichaikul, Ani A1 - Moon, Jee-Young A1 - Preuss, Michael H A1 - Ryan, Kathleen A1 - Wang, Zhe A1 - Wheeler, Marsha A1 - Yanek, Lisa R A1 - Abecasis, Goncalo R A1 - Almasy, Laura A1 - Beaty, Terri H A1 - Becker, Lewis C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Butterworth, Adam S A1 - Choquet, Helene A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Faraday, Nauder A1 - Fornage, Myriam A1 - Glahn, David C A1 - Hou, Lifang A1 - Jorgenson, Eric A1 - Kooperberg, Charles A1 - Lewis, Joshua P A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Min, Nancy A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Nickerson, Debbie A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Pankratz, Nathan A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Albert V A1 - Smith, Nicholas L A1 - Tang, Hua A1 - Tracy, Russell P A1 - Conomos, Matthew P A1 - Laurie, Cecelia A A1 - Mathias, Rasika A A1 - Li, Yun A1 - Auer, Paul L A1 - Thornton, Timothy A1 - Reiner, Alexander P A1 - Johnson, Andrew D A1 - Raffield, Laura M AB -

Platelets 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.

ER - TY - JOUR T1 - Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. JF - Genome Med Y1 - 2021 A1 - Cade, Brian E A1 - Lee, Jiwon A1 - Sofer, Tamar A1 - Wang, Heming A1 - Zhang, Man A1 - Chen, Han A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Guo, Xiuqing A1 - Lane, Jacqueline M A1 - Liang, Jingjing A1 - Lin, Xihong A1 - Mei, Hao A1 - Patel, Sanjay R A1 - Purcell, Shaun M A1 - Saxena, Richa A1 - Shah, Neomi A A1 - Evans, Daniel S A1 - Hanis, Craig L A1 - Hillman, David R A1 - Mukherjee, Sutapa A1 - Palmer, Lyle J A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Abecasis, Goncalo R A1 - Boerwinkle, Eric A A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Kaplan, Robert C A1 - Nickerson, Deborah A A1 - North, Kari E A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Zhu, Xiaofeng A1 - Redline, Susan AB -

BACKGROUND: 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.

VL - 13 IS - 1 ER - TY - JOUR T1 - Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2021 A1 - Hu, Yao A1 - Stilp, Adrienne M A1 - McHugh, Caitlin P A1 - Rao, Shuquan A1 - Jain, Deepti A1 - Zheng, Xiuwen A1 - Lane, John A1 - Méric de Bellefon, Sébastian A1 - Raffield, Laura M A1 - Chen, Ming-Huei A1 - Yanek, Lisa R A1 - Wheeler, Marsha A1 - Yao, Yao A1 - Ren, Chunyan A1 - Broome, Jai A1 - Moon, Jee-Young A1 - de Vries, Paul S A1 - Hobbs, Brian D A1 - Sun, Quan A1 - Surendran, Praveen A1 - Brody, Jennifer A A1 - Blackwell, Thomas W A1 - Choquet, Helene A1 - Ryan, Kathleen A1 - Duggirala, Ravindranath A1 - Heard-Costa, Nancy A1 - Wang, Zhe A1 - Chami, Nathalie A1 - Preuss, Michael H A1 - Min, Nancy A1 - Ekunwe, Lynette A1 - Lange, Leslie A A1 - Cushman, Mary A1 - Faraday, Nauder A1 - Curran, Joanne E A1 - Almasy, Laura A1 - Kundu, Kousik A1 - Smith, Albert V A1 - Gabriel, Stacey A1 - Rotter, Jerome I A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Vasan, Ramachandran S A1 - Smith, Nicholas L A1 - North, Kari E A1 - Boerwinkle, Eric A1 - Becker, Lewis C A1 - Lewis, Joshua P A1 - Abecasis, Goncalo R A1 - Hou, Lifang A1 - O'Connell, Jeffrey R A1 - Morrison, Alanna C A1 - Beaty, Terri H A1 - Kaplan, Robert A1 - Correa, Adolfo A1 - Blangero, John A1 - Jorgenson, Eric A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Walton, Russell T A1 - Kleinstiver, Benjamin P A1 - Tang, Hua A1 - Loos, Ruth J F A1 - Soranzo, Nicole A1 - Butterworth, Adam S A1 - Nickerson, Debbie A1 - Rich, Stephen S A1 - Mitchell, Braxton D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Li, Yun A1 - Mathias, Rasika A A1 - Lettre, Guillaume A1 - Pankratz, Nathan A1 - Laurie, Cathy C A1 - Laurie, Cecelia A A1 - Bauer, Daniel E A1 - Conomos, Matthew P A1 - Reiner, Alexander P KW - Adult KW - Aged KW - Chromosomes, Human, Pair 16 KW - Datasets as Topic KW - Erythrocytes KW - Female KW - Gene Editing KW - Genetic Variation KW - Genome-Wide Association Study KW - HEK293 Cells KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Phenotype KW - Quality Control KW - Reproducibility of Results KW - United States AB -

Whole-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.

VL - 108 IS - 5 ER - TY - JOUR T1 - Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2021 A1 - Mikhaylova, Anna V A1 - McHugh, Caitlin P A1 - Polfus, Linda M A1 - Raffield, Laura M A1 - Boorgula, Meher Preethi A1 - Blackwell, Thomas W A1 - Brody, Jennifer A A1 - Broome, Jai A1 - Chami, Nathalie A1 - Chen, Ming-Huei A1 - Conomos, Matthew P A1 - Cox, Corey A1 - Curran, Joanne E A1 - Daya, Michelle A1 - Ekunwe, Lynette A1 - Glahn, David C A1 - Heard-Costa, Nancy A1 - Highland, Heather M A1 - Hobbs, Brian D A1 - Ilboudo, Yann A1 - Jain, Deepti A1 - Lange, Leslie A A1 - Miller-Fleming, Tyne W A1 - Min, Nancy A1 - Moon, Jee-Young A1 - Preuss, Michael H A1 - Rosen, Jonathon A1 - Ryan, Kathleen A1 - Smith, Albert V A1 - Sun, Quan A1 - Surendran, Praveen A1 - de Vries, Paul S A1 - Walter, Klaudia A1 - Wang, Zhe A1 - Wheeler, Marsha A1 - Yanek, Lisa R A1 - Zhong, Xue A1 - Abecasis, Goncalo R A1 - Almasy, Laura A1 - Barnes, Kathleen C A1 - Beaty, Terri H A1 - Becker, Lewis C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Butterworth, Adam S A1 - Chavan, Sameer A1 - Cho, Michael H A1 - Choquet, Helene A1 - Correa, Adolfo A1 - Cox, Nancy A1 - DeMeo, Dawn L A1 - Faraday, Nauder A1 - Fornage, Myriam A1 - Gerszten, Robert E A1 - Hou, Lifang A1 - Johnson, Andrew D A1 - Jorgenson, Eric A1 - Kaplan, Robert A1 - Kooperberg, Charles A1 - Kundu, Kousik A1 - Laurie, Cecelia A A1 - Lettre, Guillaume A1 - Lewis, Joshua P A1 - Li, Bingshan A1 - Li, Yun A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Manichaikul, Ani A1 - Meyers, Deborah A A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Ngo, Debby A1 - Nickerson, Deborah A A1 - Nongmaithem, Suraj A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Ortega, Victor E A1 - Pankratz, Nathan A1 - Perry, James A A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Soranzo, Nicole A1 - Rotter, Jerome I A1 - Silverman, Edwin K A1 - Smith, Nicholas L A1 - Tang, Hua A1 - Tracy, Russell P A1 - Thornton, Timothy A A1 - Vasan, Ramachandran S A1 - Zein, Joe A1 - Mathias, Rasika A A1 - Reiner, Alexander P A1 - Auer, Paul L KW - Asthma KW - Biomarkers KW - Dermatitis, Atopic KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Leukocytes KW - National Heart, Lung, and Blood Institute (U.S.) KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Proteome KW - Pulmonary Disease, Chronic Obstructive KW - Quantitative Trait Loci KW - United Kingdom KW - United States KW - Whole Genome Sequencing AB -

Many 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.

VL - 108 IS - 10 ER - TY - JOUR T1 - Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. JF - Nat Genet Y1 - 2022 A1 - Wainschtein, Pierrick A1 - Jain, Deepti A1 - Zheng, Zhili A1 - Cupples, L Adrienne A1 - Shadyab, Aladdin H A1 - McKnight, Barbara A1 - Shoemaker, Benjamin M A1 - Mitchell, Braxton D A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Liu, Ching-Ti A1 - Albert, Christine M A1 - Roden, Dan A1 - Chasman, Daniel I A1 - Darbar, Dawood A1 - Lloyd-Jones, Donald M A1 - Arnett, Donna K A1 - Regan, Elizabeth A A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - O'Connell, Jeffrey R A1 - Yanek, Lisa R A1 - de Andrade, Mariza A1 - Allison, Matthew A A1 - McDonald, Merry-Lynn N A1 - Chung, Mina K A1 - Fornage, Myriam A1 - Chami, Nathalie A1 - Smith, Nicholas L A1 - Ellinor, Patrick T A1 - Vasan, Ramachandran S A1 - Mathias, Rasika A A1 - Loos, Ruth J F A1 - Rich, Stephen S A1 - Lubitz, Steven A A1 - Heckbert, Susan R A1 - Redline, Susan A1 - Guo, Xiuqing A1 - Chen, Y -D Ida A1 - Laurie, Cecelia A A1 - Hernandez, Ryan D A1 - McGarvey, Stephen T A1 - Goddard, Michael E A1 - Laurie, Cathy C A1 - North, Kari E A1 - Lange, Leslie A A1 - Weir, Bruce S A1 - Yengo, Loic A1 - Yang, Jian A1 - Visscher, Peter M AB -

Analyses 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.

VL - 54 IS - 3 ER - TY - JOUR T1 - The 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. JF - J Am Soc Echocardiogr Y1 - 2022 A1 - Barasch, Eddy A1 - Gottdiener, John S A1 - Tressel, William A1 - Bartz, Traci M A1 - Bůzková, Petra A1 - Massera, Daniele A1 - DeFilippi, Christopher A1 - Biggs, Mary L A1 - Psaty, Bruce M A1 - Kizer, Jorge R A1 - Owens, David AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - The association of hearing problems with social network strength and depressive symptoms: the cardiovascular health study. JF - Age Ageing Y1 - 2022 A1 - Dobrota, Sylvie D A1 - Biggs, Mary L A1 - Pratt, Sheila A1 - Popat, Rita A1 - Odden, Michelle C KW - Aged KW - Depression KW - Female KW - Hearing Loss KW - Humans KW - Male KW - Self Report KW - Social Networking AB -

BACKGROUND: 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.

VL - 51 IS - 8 ER - TY - JOUR T1 - Association of immune cell subsets with incident heart failure in two population-based cohorts. JF - ESC Heart Fail Y1 - 2022 A1 - Sinha, Arjun A1 - Sitlani, Colleen M A1 - Doyle, Margaret F A1 - Fohner, Alison E A1 - Bůzková, Petra A1 - Floyd, James S A1 - Huber, Sally A A1 - Olson, Nels C A1 - Njoroge, Joyce N A1 - Kizer, Jorge R A1 - Delaney, Joseph A A1 - Shah, Sanjiv S A1 - Tracy, Russell P A1 - Psaty, Bruce A1 - Feinstein, Matthew AB -

AIMS: 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.

ER - TY - JOUR T1 - Association of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study. JF - Neurology Y1 - 2022 A1 - Fohner, Alison E A1 - Bartz, Traci M A1 - Tracy, Russell P A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Djoussé, Luc A1 - Satizabal, Claudia L A1 - Lopez, Oscar L A1 - Seshadri, Sudha A1 - Mukamal, Kenneth J A1 - Kuller, Lewis H A1 - Psaty, Bruce M A1 - Longstreth, W T AB -

BACKGROUND 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.

VL - 98 IS - 9 ER - TY - JOUR T1 - Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults. JF - JAMA Netw Open Y1 - 2022 A1 - Fretts, Amanda M A1 - Hazen, Stanley L A1 - Jensen, Paul A1 - Budoff, Matthew A1 - Sitlani, Colleen M A1 - Wang, Meng A1 - de Oliveira Otto, Marcia C A1 - DiDonato, Joseph A A1 - Lee, Yujin A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Tang, W H Wilson A1 - Lai, Heidi A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Betaine KW - Cardiovascular Diseases KW - Carnitine KW - Choline KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Methylamines KW - Prospective Studies AB -

Importance: 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.

VL - 5 IS - 5 ER - TY - JOUR T1 - {An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns JF - Genome Res Y1 - 2022 A1 - Jin, B. A1 - Capra, J. A. A1 - Benchek, P. A1 - Wheeler, N. A1 - Naj, A. C. A1 - Hamilton-Nelson, K. L. A1 - Farrell, J. J. A1 - Leung, Y. Y. A1 - Kunkle, B. A1 - Vadarajan, B. A1 - Schellenberg, G. D. A1 - Mayeux, R. A1 - Wang, L. S. A1 - Farrer, L. A. A1 - Pericak-Vance, M. A. A1 - Martin, E. R. A1 - Haines, J. L. A1 - Crawford, D. C. A1 - Bush, W. S. AB - is 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. VL - 32 ER - TY - JOUR T1 - Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. JF - J Alzheimers Dis Y1 - 2022 A1 - Frenzel, Stefan A1 - Bis, Josh C A1 - Gudmundsson, Elias F A1 - O'Donnell, Adrienne A1 - Simino, Jeannette A1 - Yaqub, Amber A1 - Bartz, Traci M A1 - Brusselle, Guy G O A1 - Bülow, Robin A1 - DeCarli, Charles S A1 - Ewert, Ralf A1 - Gharib, Sina A A1 - Ghosh, Saptaparni A1 - Gireud-Goss, Monica A1 - Gottesman, Rebecca F A1 - Ikram, M Arfan A1 - Knopman, David S A1 - Launer, Lenore J A1 - London, Stephanie J A1 - Longstreth, W T A1 - Lopez, Oscar L A1 - Melo van Lent, Debora A1 - O'Connor, George A1 - Satizabal, Claudia L A1 - Shrestha, Srishti A1 - Sigurdsson, Sigurdur A1 - Stubbe, Beate A1 - Talluri, Rajesh A1 - Vasan, Ramachandran S A1 - Vernooij, Meike W A1 - Völzke, Henry A1 - Wiggins, Kerri L A1 - Yu, Bing A1 - Beiser, Alexa S A1 - Gudnason, Vilmundur A1 - Mosley, Thomas A1 - Psaty, Bruce M A1 - Wolters, Frank J A1 - Grabe, Hans J A1 - Seshadri, Sudha AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer. JF - J Nucl Med Y1 - 2022 A1 - Kunihiro, Andrew G A1 - Sarrett, Samantha M A1 - Lastwika, Kristin J A1 - Solan, Joell L A1 - Pisarenko, Tatyana A1 - Keinänen, Outi A1 - Rodriguez, Cindy A1 - Taverne, Lydia R A1 - Fitzpatrick, Annette L A1 - Li, Christopher I A1 - Houghton, A McGarry A1 - Zeglis, Brian M A1 - Lampe, Paul D KW - Animals KW - Autoantibodies KW - Biomarkers KW - Cell Line, Tumor KW - Disease Models, Animal KW - Early Detection of Cancer KW - Humans KW - Lung Neoplasms KW - Mice KW - Mice, Nude KW - Neuroendocrine Tumors KW - Positron-Emission Tomography KW - RNA, Messenger KW - Small Cell Lung Carcinoma AB -

Small 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.

VL - 63 IS - 11 ER - TY - JOUR T1 - Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2022 A1 - Durda, Peter A1 - Raffield, Laura M A1 - Lange, Ethan M A1 - Olson, Nels C A1 - Jenny, Nancy Swords A1 - Cushman, Mary A1 - Deichgraeber, Pia A1 - Grarup, Niels A1 - Jonsson, Anna A1 - Hansen, Torben A1 - Mychaleckyj, Josyf C A1 - Psaty, Bruce M A1 - Reiner, Alex P A1 - Tracy, Russell P A1 - Lange, Leslie A KW - Aged KW - Antigens, CD KW - Antigens, Differentiation, Myelomonocytic KW - Asialoglycoprotein Receptor KW - Biomarkers KW - Cardiovascular Diseases KW - Female KW - Genome-Wide Association Study KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Male AB -

Background 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.

VL - 11 IS - 21 ER - TY - JOUR T1 - Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. JF - Stroke Y1 - 2022 A1 - Bhattacharya, Romit A1 - Zekavat, Seyedeh M A1 - Haessler, Jeffrey A1 - Fornage, Myriam A1 - Raffield, Laura A1 - Uddin, Md Mesbah A1 - Bick, Alexander G A1 - Niroula, Abhishek A1 - Yu, Bing A1 - Gibson, Christopher A1 - Griffin, Gabriel A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Longstreth, William T A1 - Bis, Joshua C A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tracy, Russell P A1 - Correa, Adolfo A1 - Seshadri, Sudha A1 - Johnson, Andrew A1 - Collins, Jason M A1 - Hayden, Kathleen M A1 - Madsen, Tracy E A1 - Ballantyne, Christie M A1 - Jaiswal, Siddhartha A1 - Ebert, Benjamin L A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Whitsel, Eric A A1 - Natarajan, Pradeep A1 - Reiner, Alexander P AB -

BACKGROUND 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.

VL - 53 IS - 3 ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population. JF - Am J Kidney Dis Y1 - 2022 A1 - Kestenbaum, Bryan A1 - Bick, Alexander G A1 - Vlasschaert, Caitlyn A1 - Rauh, Michael J A1 - Lanktree, Matthew B A1 - Franceschini, Nora A1 - Shoemaker, Moore B A1 - Harris, Raymond C A1 - Psaty, Bruce M A1 - Köttgen, Anna A1 - Natarajan, Pradeep A1 - Robinson-Cohen, Cassianne AB -

RATIONALE & 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.

ER - TY - JOUR T1 - {Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease JF - Nat Commun Y1 - 2022 A1 - Uddin, M. D. M. A1 - Nguyen, N. Q. H. A1 - Yu, B. A1 - Brody, J. A. A1 - Pampana, A. A1 - Nakao, T. A1 - Fornage, M. A1 - Bressler, J. A1 - Sotoodehnia, N. A1 - Weinstock, J. S. A1 - Honigberg, M. C. A1 - Nachun, D. A1 - Bhattacharya, R. A1 - Griffin, G. K. A1 - Chander, V. A1 - Gibbs, R. A. A1 - Rotter, J. I. A1 - Liu, C. A1 - Baccarelli, A. A. A1 - Chasman, D. I. A1 - Whitsel, E. A. A1 - Kiel, D. P. A1 - Murabito, J. M. A1 - Boerwinkle, E. A1 - Ebert, B. L. A1 - Jaiswal, S. A1 - Floyd, J. S. A1 - Bick, A. G. A1 - Ballantyne, C. M. A1 - Psaty, B. M. A1 - Natarajan, P. A1 - Conneely, K. N. AB - Age-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. VL - 13 ER - TY - JOUR T1 - Correlations between complex human phenotypes vary by genetic background, gender, and environment. JF - Cell Rep Med Y1 - 2022 A1 - Elgart, Michael A1 - Goodman, Matthew O A1 - Isasi, Carmen A1 - Chen, Han A1 - Morrison, Alanna C A1 - de Vries, Paul S A1 - Xu, Huichun A1 - Manichaikul, Ani W A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lloyd-Jones, Donald M A1 - Fornage, Myriam A1 - Correa, Adolfo A1 - Heard-Costa, Nancy L A1 - Vasan, Ramachandran S A1 - Hernandez, Ryan A1 - Kaplan, Robert C A1 - Redline, Susan A1 - Sofer, Tamar KW - Female KW - Genetic Background KW - Humans KW - Male KW - Phenotype AB -

We 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.

VL - 3 IS - 12 ER - TY - JOUR T1 - Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. JF - Circulation Y1 - 2022 A1 - Thibord, Florian A1 - Klarin, Derek A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Levin, Michael G A1 - Chasman, Daniel I A1 - Goode, Ellen L A1 - Hveem, Kristian A1 - Teder-Laving, Maris A1 - Martinez-Perez, Angel A1 - Aïssi, Dylan A1 - Daian-Bacq, Delphine A1 - Ito, Kaoru A1 - Natarajan, Pradeep A1 - Lutsey, Pamela L A1 - Nadkarni, Girish N A1 - de Vries, Paul S A1 - Cuellar-Partida, Gabriel A1 - Wolford, Brooke N A1 - Pattee, Jack W A1 - Kooperberg, Charles A1 - Braekkan, Sigrid K A1 - Li-Gao, Ruifang A1 - Saut, Noémie A1 - Sept, Corriene A1 - Germain, Marine A1 - Judy, Renae L A1 - Wiggins, Kerri L A1 - Ko, Darae A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Giulianini, Franco A1 - de Andrade, Mariza A1 - Nøst, Therese H A1 - Boland, Anne A1 - Empana, Jean-Philippe A1 - Koyama, Satoshi A1 - Gilliland, Thomas A1 - Do, Ron A1 - Huffman, Jennifer E A1 - Wang, Xin A1 - Zhou, Wei A1 - Manuel Soria, Jose A1 - Carlos Souto, Juan A1 - Pankratz, Nathan A1 - Haessler, Jeffery A1 - Hindberg, Kristian A1 - Rosendaal, Frits R A1 - Turman, Constance A1 - Olaso, Robert A1 - Kember, Rachel L A1 - Bartz, Traci M A1 - Lynch, Julie A A1 - Heckbert, Susan R A1 - Armasu, Sebastian M A1 - Brumpton, Ben A1 - Smadja, David M A1 - Jouven, Xavier A1 - Komuro, Issei A1 - Clapham, Katharine R A1 - Loos, Ruth J F A1 - Willer, Cristen J A1 - Sabater-Lleal, Maria A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Morelli, Vania M A1 - Ridker, Paul M A1 - Vlieg, Astrid van Hylckama A1 - Deleuze, Jean-Francois A1 - Kraft, Peter A1 - Rader, Daniel J A1 - Min Lee, Kyung A1 - Psaty, Bruce M A1 - Heidi Skogholt, Anne A1 - Emmerich, Joseph A1 - Suchon, Pierre A1 - Rich, Stephen S A1 - Vy, Ha My T A1 - Tang, Weihong A1 - Jackson, Rebecca D A1 - Hansen, John-Bjarne A1 - Morange, Pierre-Emmanuel A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Damrauer, Scott M A1 - Johnson, Andrew D A1 - Smith, Nicholas L KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Thrombosis KW - Venous Thromboembolism AB -

BACKGROUND: 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.

VL - 146 IS - 16 ER - TY - JOUR T1 - Diabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts. JF - Circulation Y1 - 2022 A1 - Patel, Kershaw V A1 - Segar, Matthew W A1 - Lavie, Carl J A1 - Kondamudi, Nitin A1 - Neeland, Ian J A1 - Almandoz, Jaime P A1 - Martin, Corby K A1 - Carbone, Salvatore A1 - Butler, Javed A1 - Powell-Wiley, Tiffany M A1 - Pandey, Ambarish KW - Aged KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Heart Failure KW - Humans KW - Male KW - National Heart, Lung, and Blood Institute (U.S.) KW - Obesity KW - Risk Factors KW - United States AB -

BACKGROUND: 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.

VL - 145 IS - 4 ER - TY - JOUR T1 - Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2022 A1 - Wang, Meng A1 - Wang, Zeneng A1 - Lee, Yujin A1 - Lai, Heidi T M A1 - de Oliveira Otto, Marcia C A1 - Lemaitre, Rozenn N A1 - Fretts, Amanda A1 - Sotoodehnia, Nona A1 - Budoff, Matthew A1 - DiDonato, Joseph A A1 - McKnight, Barbara A1 - Tang, W H Wilson A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Hazen, Stanley L A1 - Mozaffarian, Dariush KW - Animals KW - Atherosclerosis KW - Cardiovascular Diseases KW - Carnitine KW - Humans KW - Meat KW - Methylamines KW - Risk Factors AB -

BACKGROUND: 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.

VL - 42 IS - 9 ER - TY - JOUR T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. JF - Commun Biol Y1 - 2022 A1 - Winkler, Thomas W A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Rowan, Bryce X A1 - Stanzick, Kira J A1 - Thomas, Laurent F A1 - Tin, Adrienne A1 - Hoppmann, Anselm A1 - Chu, Audrey Y A1 - Tayo, Bamidele A1 - Thio, Chris H L A1 - Cusi, Daniele A1 - Chai, Jin-Fang A1 - Sieber, Karsten B A1 - Horn, Katrin A1 - Li, Man A1 - Scholz, Markus A1 - Cocca, Massimiliano A1 - Wuttke, Matthias A1 - van der Most, Peter J A1 - Yang, Qiong A1 - Ghasemi, Sahar A1 - Nutile, Teresa A1 - Li, Yong A1 - Pontali, Giulia A1 - Günther, Felix A1 - Dehghan, Abbas A1 - Correa, Adolfo A1 - Parsa, Afshin A1 - Feresin, Agnese A1 - de Vries, Aiko P J A1 - Zonderman, Alan B A1 - Smith, Albert V A1 - Oldehinkel, Albertine J A1 - De Grandi, Alessandro A1 - Rosenkranz, Alexander R A1 - Franke, Andre A1 - Teren, Andrej A1 - Metspalu, Andres A1 - Hicks, Andrew A A1 - Morris, Andrew P A1 - Tönjes, Anke A1 - Morgan, Anna A1 - Podgornaia, Anna I A1 - Peters, Annette A1 - Körner, Antje A1 - Mahajan, Anubha A1 - Campbell, Archie A1 - Freedman, Barry I A1 - Spedicati, Beatrice A1 - Ponte, Belen A1 - Schöttker, Ben A1 - Brumpton, Ben A1 - Banas, Bernhard A1 - Krämer, Bernhard K A1 - Jung, Bettina A1 - Åsvold, Bjørn Olav A1 - Smith, Blair H A1 - Ning, Boting A1 - Penninx, Brenda W J H A1 - Vanderwerff, Brett R A1 - Psaty, Bruce M A1 - Kammerer, Candace M A1 - Langefeld, Carl D A1 - Hayward, Caroline A1 - Spracklen, Cassandra N A1 - Robinson-Cohen, Cassianne A1 - Hartman, Catharina A A1 - Lindgren, Cecilia M A1 - Wang, Chaolong A1 - Sabanayagam, Charumathi A1 - Heng, Chew-Kiat A1 - Lanzani, Chiara A1 - Khor, Chiea-Chuen A1 - Cheng, Ching-Yu A1 - Fuchsberger, Christian A1 - Gieger, Christian A1 - Shaffer, Christian M A1 - Schulz, Christina-Alexandra A1 - Willer, Cristen J A1 - Chasman, Daniel I A1 - Gudbjartsson, Daniel F A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Czamara, Darina A1 - Porteous, David J A1 - Waterworth, Dawn M A1 - Mascalzoni, Deborah A1 - Mook-Kanamori, Dennis O A1 - Reilly, Dermot F A1 - Daw, E Warwick A1 - Hofer, Edith A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Tai, E-Shyong A1 - Catamo, Eulalia A1 - Rizzi, Federica A1 - Guo, Feng A1 - Rivadeneira, Fernando A1 - Guilianini, Franco A1 - Sveinbjornsson, Gardar A1 - Ehret, Georg A1 - Waeber, Gérard A1 - Biino, Ginevra A1 - Girotto, Giorgia A1 - Pistis, Giorgio A1 - Nadkarni, Girish N A1 - Delgado, Graciela E A1 - Montgomery, Grant W A1 - Snieder, Harold A1 - Campbell, Harry A1 - White, Harvey D A1 - Gao, He A1 - Stringham, Heather M A1 - Schmidt, Helena A1 - Li, Hengtong A1 - Brenner, Hermann A1 - Holm, Hilma A1 - Kirsten, Holgen A1 - Kramer, Holly A1 - Rudan, Igor A1 - Nolte, Ilja M A1 - Tzoulaki, Ioanna A1 - Olafsson, Isleifur A1 - Martins, Jade A1 - Cook, James P A1 - Wilson, James F A1 - Halbritter, Jan A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Kooner, Jaspal S A1 - Lee, Jeannette Jen-Mai A1 - O'Connell, Jeffrey A1 - Rotter, Jerome I A1 - Liu, Jianjun A1 - Xu, Jie A1 - Thiery, Joachim A1 - Arnlöv, Johan A1 - Kuusisto, Johanna A1 - Jakobsdottir, Johanna A1 - Tremblay, Johanne A1 - Chambers, John C A1 - Whitfield, John B A1 - Gaziano, John M A1 - Marten, Jonathan A1 - Coresh, Josef A1 - Jonas, Jost B A1 - Mychaleckyj, Josyf C A1 - Christensen, Kaare A1 - Eckardt, Kai-Uwe A1 - Mohlke, Karen L A1 - Endlich, Karlhans A1 - Dittrich, Katalin A1 - Ryan, Kathleen A A1 - Rice, Kenneth M A1 - Taylor, Kent D A1 - Ho, Kevin A1 - Nikus, Kjell A1 - Matsuda, Koichi A1 - Strauch, Konstantin A1 - Miliku, Kozeta A1 - Hveem, Kristian A1 - Lind, Lars A1 - Wallentin, Lars A1 - Yerges-Armstrong, Laura M A1 - Raffield, Laura M A1 - Phillips, Lawrence S A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Lange, Leslie A A1 - Citterio, Lorena A1 - Klaric, Lucija A1 - Ikram, M Arfan A1 - Ising, Marcus A1 - Kleber, Marcus E A1 - Francescatto, Margherita A1 - Concas, Maria Pina A1 - Ciullo, Marina A1 - Piratsu, Mario A1 - Orho-Melander, Marju A1 - Laakso, Markku A1 - Loeffler, Markus A1 - Perola, Markus A1 - de Borst, Martin H A1 - Gögele, Martin A1 - Bianca, Martina La A1 - Lukas, Mary Ann A1 - Feitosa, Mary F A1 - Biggs, Mary L A1 - Wojczynski, Mary K A1 - Kavousi, Maryam A1 - Kanai, Masahiro A1 - Akiyama, Masato A1 - Yasuda, Masayuki A1 - Nauck, Matthias A1 - Waldenberger, Melanie A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Boehnke, Michael A1 - Preuss, Michael H A1 - Stumvoll, Michael A1 - Province, Michael A A1 - Evans, Michele K A1 - O'Donoghue, Michelle L A1 - Kubo, Michiaki A1 - Kähönen, Mika A1 - Kastarinen, Mika A1 - Nalls, Mike A A1 - Kuokkanen, Mikko A1 - Ghanbari, Mohsen A1 - Bochud, Murielle A1 - Josyula, Navya Shilpa A1 - Martin, Nicholas G A1 - Tan, Nicholas Y Q A1 - Palmer, Nicholette D A1 - Pirastu, Nicola A1 - Schupf, Nicole A1 - Verweij, Niek A1 - Hutri-Kähönen, Nina A1 - Mononen, Nina A1 - Bansal, Nisha A1 - Devuyst, Olivier A1 - Melander, Olle A1 - Raitakari, Olli T A1 - Polasek, Ozren A1 - Manunta, Paolo A1 - Gasparini, Paolo A1 - Mishra, Pashupati P A1 - Sulem, Patrick A1 - Magnusson, Patrik K E A1 - Elliott, Paul A1 - Ridker, Paul M A1 - Hamet, Pavel A1 - Svensson, Per O A1 - Joshi, Peter K A1 - Kovacs, Peter A1 - Pramstaller, Peter P A1 - Rossing, Peter A1 - Vollenweider, Peter A1 - van der Harst, Pim A1 - Dorajoo, Rajkumar A1 - Sim, Ralene Z H A1 - Burkhardt, Ralph A1 - Tao, Ran A1 - Noordam, Raymond A1 - Mägi, Reedik A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Rueedi, Rico A1 - van Dam, Rob M A1 - Carroll, Robert J A1 - Gansevoort, Ron T A1 - Loos, Ruth J F A1 - Felicita, Sala Cinzia A1 - Sedaghat, Sanaz A1 - Padmanabhan, Sandosh A1 - Freitag-Wolf, Sandra A1 - Pendergrass, Sarah A A1 - Graham, Sarah E A1 - Gordon, Scott D A1 - Hwang, Shih-Jen A1 - Kerr, Shona M A1 - Vaccargiu, Simona A1 - Patil, Snehal B A1 - Hallan, Stein A1 - Bakker, Stephan J L A1 - Lim, Su-Chi A1 - Lucae, Susanne A1 - Vogelezang, Suzanne A1 - Bergmann, Sven A1 - Corre, Tanguy A1 - Ahluwalia, Tarunveer S A1 - Lehtimäki, Terho A1 - Boutin, Thibaud S A1 - Meitinger, Thomas A1 - Wong, Tien-Yin A1 - Bergler, Tobias A1 - Rabelink, Ton J A1 - Esko, Tõnu A1 - Haller, Toomas A1 - Thorsteinsdottir, Unnur A1 - Völker, Uwe A1 - Foo, Valencia Hui Xian A1 - Salomaa, Veikko A1 - Vitart, Veronique A1 - Giedraitis, Vilmantas A1 - Gudnason, Vilmundur A1 - Jaddoe, Vincent W V A1 - Huang, Wei A1 - Zhang, Weihua A1 - Wei, Wen Bin A1 - Kiess, Wieland A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Gào, Xīn A1 - Sim, Xueling A1 - Wang, Ya Xing A1 - Friedlander, Yechiel A1 - Tham, Yih-Chung A1 - Kamatani, Yoichiro A1 - Okada, Yukinori A1 - Milaneschi, Yuri A1 - Yu, Zhi A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Hung, Adriana M A1 - Kronenberg, Florian A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Heid, Iris M KW - Creatinine KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney AB -

Reduced 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.

VL - 5 IS - 1 ER - TY - JOUR T1 - {DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases JF - Nat Commun Y1 - 2022 A1 - Wielscher, M. A1 - Mandaviya, P. R. A1 - Kuehnel, B. A1 - Joehanes, R. A1 - Mustafa, R. A1 - Robinson, O. A1 - Zhang, Y. A1 - Bodinier, B. A1 - Walton, E. A1 - Mishra, P. P. A1 - Schlosser, P. A1 - Wilson, R. A1 - Tsai, P. C. A1 - Palaniswamy, S. A1 - Marioni, R. E. A1 - Fiorito, G. A1 - Cugliari, G. A1 - Karhunen, V. A1 - Ghanbari, M. A1 - Psaty, B. M. A1 - Loh, M. A1 - Bis, J. C. A1 - Lehne, B. A1 - Sotoodehnia, N. A1 - Deary, I. J. A1 - Chadeau-Hyam, M. A1 - Brody, J. A. A1 - Cardona, A. A1 - Selvin, E. A1 - Smith, A. K. A1 - Miller, A. H. A1 - Torres, M. A. A1 - Marouli, E. A1 - Gào, X. A1 - van Meurs, J. B. J. A1 - Graf-Schindler, J. A1 - Rathmann, W. A1 - Koenig, W. A1 - Peters, A. A1 - Weninger, W. A1 - Farlik, M. A1 - Zhang, T. A1 - Chen, W. A1 - Xia, Y. A1 - Teumer, A. A1 - Nauck, M. A1 - Grabe, H. J. A1 - Doerr, M. A1 - Lehtimäki, T. A1 - Guan, W. A1 - Milani, L. A1 - Tanaka, T. A1 - Fisher, K. A1 - Waite, L. L. A1 - Kasela, S. A1 - Vineis, P. A1 - Verweij, N. A1 - van der Harst, P. A1 - Iacoviello, L. A1 - Sacerdote, C. A1 - Panico, S. A1 - Krogh, V. A1 - Tumino, R. A1 - Tzala, E. A1 - Matullo, G. A1 - Hurme, M. A. A1 - Raitakari, O. T. A1 - Colicino, E. A1 - Baccarelli, A. A. A1 - Kähönen, M. A1 - Herzig, K. H. A1 - Li, S. A1 - Conneely, K. N. A1 - Kooner, J. S. A1 - Köttgen, A. A1 - Heijmans, B. T. A1 - Deloukas, P. A1 - Relton, C. A1 - Ong, K. K. A1 - Bell, J. T. A1 - Boerwinkle, E. A1 - Elliott, P. A1 - Brenner, H. A1 - Beekman, M. A1 - Levy, D. A1 - Waldenberger, M. A1 - Chambers, J. C. A1 - Dehghan, A. A1 - Jarvelin, M. R. AB - We 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. VL - 13 ER - TY - JOUR T1 - Dysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age. JF - Heart Y1 - 2022 A1 - Pellegrini, Cara N A1 - Bůzková, Petra A1 - Oesterle, Adam A1 - Heckbert, Susan R A1 - Tracy, Russell P A1 - Siscovick, David S A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Kizer, Jorge R AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. JF - Nat Commun Y1 - 2022 A1 - Halford, Jennifer L A1 - Morrill, Valerie N A1 - Choi, Seung Hoan A1 - Jurgens, Sean J A1 - Melloni, Giorgio A1 - Marston, Nicholas A A1 - Weng, Lu-Chen A1 - Nauffal, Victor A1 - Hall, Amelia W A1 - Gunn, Sophia A1 - Austin-Tse, Christina A A1 - Pirruccello, James P A1 - Khurshid, Shaan A1 - Rehm, Heidi L A1 - Benjamin, Emelia J A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Correa, Adolfo A1 - Fornwalt, Brandon K A1 - Gupta, Namrata A1 - Haggerty, Christopher M A1 - Harris, Stephanie A1 - Heckbert, Susan R A1 - Hong, Charles C A1 - Kooperberg, Charles A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Post, Wendy A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schnatz, Peter F A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Wong, Eugene K A1 - Sabatine, Marc S A1 - Ruff, Christian T A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T A1 - Lubitz, Steven A KW - Disease Susceptibility KW - Endophenotypes KW - Humans KW - Long QT Syndrome KW - Virulence AB -

Accurate 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.

VL - 13 IS - 1 ER - TY - JOUR T1 - Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. JF - Brain Y1 - 2022 A1 - Yang, Yunju A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Mishra, Aniket A1 - Liu, Dan A1 - Luciano, Michelle A1 - Teumer, Alexander A1 - Armstrong, Nicola A1 - Bis, Joshua C A1 - Jhun, Min A A1 - Li, Shuo A1 - Adams, Hieab H H A1 - Aziz, Nasir Ahmad A1 - Bastin, Mark E A1 - Bourgey, Mathieu A1 - Brody, Jennifer A A1 - Frenzel, Stefan A1 - Gottesman, Rebecca F A1 - Hosten, Norbert A1 - Hou, Lifang A1 - Kardia, Sharon L R A1 - Lohner, Valerie A1 - Marquis, Pascale A1 - Maniega, Susana Muñoz A1 - Satizabal, Claudia L A1 - Sorond, Farzaneh A A1 - Valdés Hernández, Maria C A1 - van Duijn, Cornelia M A1 - Vernooij, Meike W A1 - Wittfeld, Katharina A1 - Yang, Qiong A1 - Zhao, Wei A1 - Boerwinkle, Eric A1 - Levy, Daniel A1 - Deary, Ian J A1 - Jiang, Jiyang A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Sachdev, Perminder S A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - DeCarli, Charles S A1 - Breteler, Monique M B A1 - Arfan Ikram, M A1 - Grabe, Hans J A1 - Wardlaw, Joanna A1 - Longstreth, W T A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Debette, Stephanie A1 - Fornage, Myriam AB -

Cerebral 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.

ER - TY - JOUR T1 - Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and its Subtypes in Older Adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2022 A1 - Oesterle, Adam A1 - Bůzková, Petra A1 - Pellegrini, Cara A1 - Hirsch, Calvin A1 - Tracy, Russell P A1 - Siscovick, David S A1 - Djoussé, Luc A1 - Mukamal, Ken J A1 - Kizer, Jorge R AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Fishing for health: Neighborhood variation in fish intake, fish quality and association with stroke risk among older adults in the Cardiovascular Health Study. JF - Nutr Metab Cardiovasc Dis Y1 - 2022 A1 - Liang, Li-Jung A1 - Casillas, Alejandra A1 - Longstreth, W T A1 - PhanVo, Lynn A1 - Vassar, Stefanie D A1 - Brown, Arleen F AB -

BACKGROUND 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.

ER - TY - JOUR T1 - A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. JF - Nat Methods Y1 - 2022 A1 - Li, Zilin A1 - Li, Xihao A1 - Zhou, Hufeng A1 - Gaynor, Sheila M A1 - Selvaraj, Margaret Sunitha A1 - Arapoglou, Theodore A1 - Quick, Corbin A1 - Liu, Yaowu A1 - Chen, Han A1 - Sun, Ryan A1 - Dey, Rounak A1 - Arnett, Donna K A1 - Auer, Paul L A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blackwell, Thomas W A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Conomos, Matthew P A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Duggirala, Ravindranath A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Göring, Harald H H A1 - Guo, Xiuqing A1 - Kalyani, Rita R A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Lange, Leslie A A1 - Lin, Bridget M A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Meigs, James B A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Taub, Margaret A A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Wilson, James G A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Willer, Cristen J A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Lin, Xihong KW - Genetic Variation KW - Genome KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Whole Genome Sequencing AB -

Large-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.

VL - 19 IS - 12 ER - TY - JOUR T1 - {Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy JF - Am J Ophthalmol Y1 - 2022 A1 - Sobrin, L. A1 - Susarla, G. A1 - Stanwyck, L. A1 - Rouhana, J. M. A1 - Li, A. A1 - Pollack, S. A1 - Igo, R. P. A1 - Jensen, R. A. A1 - Li, X. A1 - Ng, M. C. Y. A1 - Smith, A. V. A1 - Kuo, J. Z. A1 - Taylor, K. D. A1 - Freedman, B. I. A1 - Bowden, D. W. A1 - Penman, A. A1 - Chen, C. J. A1 - Craig, J. E. A1 - Adler, S. G. A1 - Chew, E. Y. A1 - Cotch, M. F. A1 - Yaspan, B. A1 - Mitchell, P. A1 - Wang, J. J. A1 - Klein, B. E. K. A1 - Wong, T. Y. A1 - Rotter, J. I. A1 - Burdon, K. P. A1 - Iyengar, S. K. A1 - Segrè, A. V. AB - {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 enrichment VL - 233 ER - TY - JOUR T1 - {Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate JF - Brain Y1 - 2022 A1 - Mishra, A. A1 - Duplaà, C. A1 - Vojinovic, D. A1 - Suzuki, H. A1 - Sargurupremraj, M. A1 - Zilhao, N. R. A1 - Li, S. A1 - Bartz, T. M. A1 - Jian, X. A1 - Zhao, W. A1 - Hofer, E. A1 - Wittfeld, K. A1 - Harris, S. E. A1 - van der Auwera-Palitschka, S. A1 - Luciano, M. A1 - Bis, J. C. A1 - Adams, H. H. H. A1 - Satizabal, C. L. A1 - Gottesman, R. F. A1 - Gampawar, P. G. A1 - Bülow, R. A1 - Weiss, S. A1 - Yu, M. A1 - Bastin, M. E. A1 - Lopez, O. L. A1 - Vernooij, M. W. A1 - Beiser, A. S. A1 - Völker, U. A1 - Kacprowski, T. A1 - Soumare, A. A1 - Smith, J. A. A1 - Knopman, D. S. A1 - Morris, Z. A1 - Zhu, Y. A1 - Rotter, J. I. A1 - Dufouil, C. A1 - Valdés Hernández, M. A1 - Muñoz Maniega, S. A1 - Lathrop, M. A1 - Boerwinkle, E. A1 - Schmidt, R. A1 - Ihara, M. A1 - Mazoyer, B. A1 - Yang, Q. A1 - Joutel, A. A1 - Tournier-Lasserve, E. A1 - Launer, L. J. A1 - Deary, I. J. A1 - Mosley, T. H. A1 - Amouyel, P. A1 - DeCarli, C. S. A1 - Psaty, B. M. A1 - Tzourio, C. A1 - Kardia, S. L. R. A1 - Grabe, H. J. A1 - Teumer, A. A1 - van Duijn, C. M. A1 - Schmidt, H. A1 - Wardlaw, J. M. A1 - Ikram, M. A. A1 - Fornage, M. A1 - Gudnason, V. A1 - Seshadri, S. A1 - Matthews, P. M. A1 - Longstreth, W. T. A1 - Couffinhal, T. A1 - Debette, S. AB - Cerebral 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. VL - 145 ER - TY - JOUR T1 - {Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways JF - Nat Commun Y1 - 2022 A1 - Young, W. J. A1 - Lahrouchi, N. A1 - Isaacs, A. A1 - Duong, T. A1 - Foco, L. A1 - Ahmed, F. A1 - Brody, J. A. A1 - Salman, R. A1 - Noordam, R. A1 - Benjamins, J. W. A1 - Haessler, J. A1 - Lyytikäinen, L. P. A1 - Repetto, L. A1 - Concas, M. P. A1 - van den Berg, M. E. A1 - Weiss, S. A1 - Baldassari, A. R. A1 - Bartz, T. M. A1 - Cook, J. P. A1 - Evans, D. S. A1 - Freudling, R. A1 - Hines, O. A1 - Isaksen, J. L. A1 - Lin, H. A1 - Mei, H. A1 - Moscati, A. A1 - Müller-Nurasyid, M. A1 - Nursyifa, C. A1 - Qian, Y. A1 - Richmond, A. A1 - Roselli, C. A1 - Ryan, K. A. A1 - Tarazona-Santos, E. A1 - Thériault, S. A1 - van Duijvenboden, S. A1 - Warren, H. R. A1 - Yao, J. A1 - Raza, D. A1 - Aeschbacher, S. A1 - Ahlberg, G. A1 - Alonso, A. A1 - Andreasen, L. A1 - Bis, J. C. A1 - Boerwinkle, E. A1 - Campbell, A. A1 - Catamo, E. A1 - Cocca, M. A1 - Cutler, M. J. A1 - Darbar, D. A1 - De Grandi, A. A1 - De Luca, A. A1 - Ding, J. A1 - Ellervik, C. A1 - Ellinor, P. T. A1 - Felix, S. B. A1 - Froguel, P. A1 - Fuchsberger, C. A1 - Gögele, M. A1 - Graff, C. A1 - Graff, M. A1 - Guo, X. A1 - Hansen, T. A1 - Heckbert, S. R. A1 - Huang, P. L. A1 - Huikuri, H. V. A1 - Hutri-Kähönen, N. A1 - Ikram, M. A. A1 - Jackson, R. D. A1 - Junttila, J. A1 - Kavousi, M. A1 - Kors, J. A. A1 - Leal, T. P. A1 - Lemaitre, R. N. A1 - Lin, H. J. A1 - Lind, L. A1 - Linneberg, A. A1 - Liu, S. A1 - Macfarlane, P. W. A1 - Mangino, M. A1 - Meitinger, T. A1 - Mezzavilla, M. A1 - Mishra, P. P. A1 - Mitchell, R. N. A1 - Mononen, N. A1 - Montasser, M. E. A1 - Morrison, A. C. A1 - Nauck, M. A1 - Nauffal, V. A1 - Navarro, P. A1 - Nikus, K. A1 - Pare, G. A1 - Patton, K. K. A1 - Pelliccione, G. A1 - Pittman, A. A1 - Porteous, D. J. A1 - Pramstaller, P. P. A1 - Preuss, M. H. A1 - Raitakari, O. T. A1 - Reiner, A. P. A1 - Ribeiro, A. L. P. A1 - Rice, K. M. A1 - Risch, L. A1 - Schlessinger, D. A1 - Schotten, U. A1 - Schurmann, C. A1 - Shen, X. A1 - Shoemaker, M. B. A1 - Sinagra, G. A1 - Sinner, M. F. A1 - Soliman, E. Z. A1 - Stoll, M. A1 - Strauch, K. A1 - Tarasov, K. A1 - Taylor, K. D. A1 - Tinker, A. A1 - Trompet, S. A1 - Uitterlinden, A. A1 - Völker, U. A1 - Völzke, H. A1 - Waldenberger, M. A1 - Weng, L. C. A1 - Whitsel, E. A. A1 - Wilson, J. G. A1 - Avery, C. L. A1 - Conen, D. A1 - Correa, A. A1 - Cucca, F. A1 - Dörr, M. A1 - Gharib, S. A. A1 - Girotto, G. A1 - Grarup, N. A1 - Hayward, C. A1 - Jamshidi, Y. A1 - Jarvelin, M. R. A1 - Jukema, J. W. A1 - Kääb, S. A1 - Kähönen, M. A1 - Kanters, J. K. A1 - Kooperberg, C. A1 - Lehtimäki, T. A1 - Lima-Costa, M. F. A1 - Liu, Y. A1 - Loos, R. J. F. A1 - Lubitz, S. A. A1 - Mook-Kanamori, D. O. A1 - Morris, A. P. A1 - O'Connell, J. R. A1 - Olesen, M. S. A1 - Orini, M. A1 - Padmanabhan, S. A1 - Pattaro, C. A1 - Peters, A. A1 - Psaty, B. M. A1 - Rotter, J. I. A1 - Stricker, B. A1 - van der Harst, P. A1 - van Duijn, C. M. A1 - Verweij, N. A1 - Wilson, J. F. A1 - Arking, D. E. A1 - Ramirez, J. A1 - Lambiase, P. D. A1 - Sotoodehnia, N. A1 - Mifsud, B. A1 - Newton-Cheh, C. A1 - Munroe, P. B. AB - 250,000 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. VL - 13 ER - TY - JOUR T1 - {Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study JF - Hum Mol Genet Y1 - 2022 A1 - Portilla-Fernandez, E. A1 - Klarin, D. A1 - Hwang, S. J. A1 - Biggs, M. L. A1 - Bis, J. C. A1 - Weiss, S. A1 - Rospleszcz, S. A1 - Natarajan, P. A1 - Hoffmann, U. A1 - Rogers, I. S. A1 - Truong, Q. A. A1 - lker, U. A1 - rr, M. A1 - low, R. A1 - Criqui, M. H. A1 - Allison, M. A1 - Ganesh, S. K. A1 - Yao, J. A1 - Waldenberger, M. A1 - Bamberg, F. A1 - Rice, K. M. A1 - Essers, J. A1 - Kapteijn, D. M. C. A1 - van der Laan, S. W. A1 - de Knegt, R. J. A1 - Ghanbari, M. A1 - Felix, J. F. A1 - Ikram, M. A. A1 - Kavousi, M. A1 - Uitterlinden, A. G. A1 - Roks, A. J. M. A1 - Danser, A. H. J. A1 - Tsao, P. S. A1 - Damrauer, S. M. A1 - Guo, X. A1 - Rotter, J. I. A1 - Psaty, B. M. A1 - Kathiresan, S. A1 - lzke, H. A1 - Peters, A. A1 - Johnson, C. A1 - Strauch, K. A1 - Meitinger, T. A1 - O'Donnell, C. J. A1 - Dehghan, A. AB - 0.0001), 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. VL - 31 ER - TY - JOUR T1 - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. JF - Kidney Int Y1 - 2022 A1 - Gorski, Mathias A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Thomas, Laurent F A1 - Graham, Sarah E A1 - Sveinbjornsson, Gardar A1 - Winkler, Thomas W A1 - Günther, Felix A1 - Stark, Klaus J A1 - Chai, Jin-Fang A1 - Tayo, Bamidele O A1 - Wuttke, Matthias A1 - Li, Yong A1 - Tin, Adrienne A1 - Ahluwalia, Tarunveer S A1 - Arnlöv, Johan A1 - Åsvold, Bjørn Olav A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Böhnke, Michael A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Carroll, Robert J A1 - Chaker, Layal A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Chu, Audrey Y A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Cook, James P A1 - Coresh, Josef A1 - Cusi, Daniele A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Feitosa, Mary F A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Fuchsberger, Christian A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hishida, Asahi A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Karabegović, Irma A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Li, Man A1 - Lieb, Wolfgang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Matias-Garcia, Pamela R A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Naito, Mariko A1 - Nakatochi, Masahiro A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - O'Donoghue, Michelle L A1 - O'Connell, Jeffrey A1 - Olafsson, Isleifur A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Pirastu, Mario A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Sabanayagam, Charumathi A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scholz, Markus A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Sieber, Karsten B A1 - Sim, Xueling A1 - Sims, Mario A1 - Snieder, Harold A1 - Stanzick, Kira J A1 - Thorsteinsdottir, Unnur A1 - Stocker, Hannah A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Sulem, Patrick A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Thio, Chris H L A1 - Tremblay, Johanne A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Wakai, Kenji A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wallner, Stefan A1 - Wang, Judy A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Willer, Cristen J A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yerges-Armstrong, Laura M A1 - Zimmermann, Martina A1 - Zonderman, Alan B A1 - Bergler, Tobias A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Heid, Iris M AB -

Estimated 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.

ER - TY - JOUR T1 - Genome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus. JF - Circ Res Y1 - 2022 A1 - Downie, Carolina G A1 - Highland, Heather M A1 - Lee, Moa P A1 - Raffield, Laura M A1 - Preuss, Michael A1 - Whitsel, Eric A A1 - Psaty, Bruce M A1 - Sitlani, Colleen M A1 - Graff, Mariaelisa A1 - Avery, Christy L KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diuretics KW - Genome-Wide Association Study KW - Sodium Chloride Symporter Inhibitors KW - Thiazides KW - Triglycerides VL - 131 IS - 3 ER - TY - JOUR T1 - Genome-wide analyses identify as a susceptibility locus for premature atrial contraction frequency. JF - iScience Y1 - 2022 A1 - Thériault, Sébastien A1 - Imboden, Medea A1 - Biggs, Mary L A1 - Austin, Thomas R A1 - Aeschbacher, Stefanie A1 - Schaffner, Emmanuel A1 - Brody, Jennifer A A1 - Bartz, Traci M A1 - Risch, Martin A1 - Grossmann, Kirsten A1 - Lin, Henry J A1 - Soliman, Elsayed Z A1 - Post, Wendy S A1 - Risch, Lorenz A1 - Krieger, Jose E A1 - Pereira, Alexandre C A1 - Heckbert, Susan R A1 - Sotoodehnia, Nona A1 - Probst-Hensch, Nicole M A1 - Conen, David AB -

Premature 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.

VL - 25 IS - 10 ER - TY - JOUR T1 - {Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation JF - Hum Genet Y1 - 2022 A1 - Longchamps, R. J. A1 - Yang, S. Y. A1 - Castellani, C. A. A1 - Shi, W. A1 - Lane, J. A1 - Grove, M. L. A1 - Bartz, T. M. A1 - Sarnowski, C. A1 - Liu, C. A1 - Burrows, K. A1 - Guyatt, A. L. A1 - Gaunt, T. R. A1 - Kacprowski, T. A1 - Yang, J. A1 - De Jager, P. L. A1 - Yu, L. A1 - Bergman, A. A1 - Xia, R. A1 - Fornage, M. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - Kraja, A. T. A1 - Province, M. A. A1 - Amin, N. A1 - Rivadeneira, F. A1 - Tiemeier, H. A1 - Uitterlinden, A. G. A1 - Broer, L. A1 - van Meurs, J. B. J. A1 - van Duijn, C. M. A1 - Raffield, L. M. A1 - Lange, L. A1 - Rich, S. S. A1 - Lemaitre, R. N. A1 - Goodarzi, M. O. A1 - Sitlani, C. M. A1 - Mak, A. C. Y. A1 - Bennett, D. A. A1 - Rodriguez, S. A1 - Murabito, J. M. A1 - Lunetta, K. L. A1 - Sotoodehnia, N. A1 - Atzmon, G. A1 - Ye, K. A1 - Barzilai, N. A1 - Brody, J. A. A1 - Psaty, B. M. A1 - Taylor, K. D. A1 - Rotter, J. I. A1 - Boerwinkle, E. A1 - Pankratz, N. A1 - Arking, D. E. AB - ). VL - 141 ER - TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Mol Psychiatry Y1 - 2022 A1 - Lahti, Jari A1 - Tuominen, Samuli A1 - Yang, Qiong A1 - Pergola, Giulio A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Armstrong, Nicola J A1 - Beiser, Alexa A1 - Bey, Katharina A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chen, Qiang A1 - Corley, Janie A1 - Cox, Simon R A1 - Davies, Gail A1 - De Jager, Philip L A1 - Derks, Eske M A1 - Faul, Jessica D A1 - Fitzpatrick, Annette L A1 - Fohner, Alison E A1 - Ford, Ian A1 - Fornage, Myriam A1 - Gerring, Zachary A1 - Grabe, Hans J A1 - Grodstein, Francine A1 - Gudnason, Vilmundur A1 - Simonsick, Eleanor A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kajantie, Eero A1 - Kaprio, Jaakko A1 - Karell, Pauliina A1 - Kleineidam, Luca A1 - Knol, Maria J A1 - Kochan, Nicole A A1 - Kwok, John B A1 - Leber, Markus A1 - Lam, Max A1 - Lee, Teresa A1 - Li, Shuo A1 - Loukola, Anu A1 - Luck, Tobias A1 - Marioni, Riccardo E A1 - Mather, Karen A A1 - Medland, Sarah A1 - Mirza, Saira S A1 - Nalls, Mike A A1 - Nho, Kwangsik A1 - O'Donnell, Adrienne A1 - Oldmeadow, Christopher A1 - Painter, Jodie A1 - Pattie, Alison A1 - Reppermund, Simone A1 - Risacher, Shannon L A1 - Rose, Richard J A1 - Sadashivaiah, Vijay A1 - Scholz, Markus A1 - Satizabal, Claudia L A1 - Schofield, Peter W A1 - Schraut, Katharina E A1 - Scott, Rodney J A1 - Simino, Jeannette A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Stott, David J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Villringer, Arno A1 - Völker, Uwe A1 - Wilson, Robert S A1 - Wittfeld, Katharina A1 - Vuoksimaa, Eero A1 - Xia, Rui A1 - Yaffe, Kristine A1 - Yu, Lei A1 - Zare, Habil A1 - Zhao, Wei A1 - Ames, David A1 - Attia, John A1 - Bennett, David A A1 - Brodaty, Henry A1 - Chasman, Daniel I A1 - Goldman, Aaron L A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon L R A1 - Lencz, Todd A1 - Loeffler, Markus A1 - Mattay, Venkata S A1 - Palotie, Aarno A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Ridker, Paul M A1 - Riedel-Heller, Steffi G A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Scherer, Martin A1 - Schofield, Peter R A1 - Sidney, Stephen A1 - Starr, John M A1 - Trollor, Julian A1 - Ulrich, William A1 - Wagner, Michael A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stephanie A1 - Eriksson, Johan G A1 - Mosley, Thomas H A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Deary, Ian J A1 - Seshadri, Sudha A1 - Räikkönen, Katri AB -

Understanding 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.

ER - TY - JOUR T1 - {Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases JF - JCI Insight Y1 - 2022 A1 - Li, Y. A1 - Cheng, Y. A1 - Consolato, F. A1 - Schiano, G. A1 - Chong, M. R. A1 - Pietzner, M. A1 - Nguyen, N. Q. H. A1 - Scherer, N. A1 - Biggs, M. L. A1 - Kleber, M. E. A1 - Haug, S. A1 - Göçmen, B. A1 - Pigeyre, M. A1 - Sekula, P. A1 - Steinbrenner, I. A1 - Schlosser, P. A1 - Joseph, C. B. A1 - Brody, J. A. A1 - Grams, M. E. A1 - Hayward, C. A1 - Schultheiss, U. T. A1 - Krämer, B. K. A1 - Kronenberg, F. A1 - Peters, A. A1 - Seissler, J. A1 - Steubl, D. A1 - Then, C. A1 - Wuttke, M. A1 - März, W. A1 - Eckardt, K. U. A1 - Gieger, C. A1 - Boerwinkle, E. A1 - Psaty, B. M. A1 - Coresh, J. A1 - Oefner, P. J. A1 - Pare, G. A1 - Langenberg, C. A1 - Scherberich, J. E. A1 - Yu, B. A1 - Akilesh, S. A1 - Devuyst, O. A1 - Rampoldi, L. A1 - Köttgen, A. AB - Uromodulin (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. VL - 7 ER - TY - JOUR T1 - Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study. JF - Cardiovasc Diabetol Y1 - 2022 A1 - Garg, Parveen K A1 - Biggs, Mary L A1 - Kizer, Jorge R A1 - Shah, Sanjiv J A1 - Psaty, Bruce A1 - Carnethon, Mercedes A1 - Gottdiener, John S A1 - Siscovick, David A1 - Mukamal, Kenneth J KW - Aged KW - Cross-Sectional Studies KW - Female KW - Glucose KW - Humans KW - Insulin Resistance KW - Male KW - Ventricular Dysfunction, Left KW - Ventricular Function, Left AB -

OBJECTIVE: 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.

VL - 21 IS - 1 ER - TY - JOUR T1 - Immune cell subpopulations as risk factors for atrial fibrillation: The Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis. JF - Heart Rhythm Y1 - 2022 A1 - Floyd, James S A1 - Sitlani, Colleen M A1 - Doyle, Margaret F A1 - Feinstein, Matthew J A1 - Olson, Nels C A1 - Heckbert, Susan R A1 - Huber, Sally A A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Delaney, Joseph A C ER - TY - JOUR T1 - The Impact of Time Horizon on Classification Accuracy: Application of Machine Learning to Prediction of Incident Coronary Heart Disease. JF - JMIR Cardio Y1 - 2022 A1 - Simon, Steven A1 - Mandair, Divneet A1 - Albakri, Abdel A1 - Fohner, Alison A1 - Simon, Noah A1 - Lange, Leslie A1 - Biggs, Mary A1 - Mukamal, Kenneth A1 - Psaty, Bruce A1 - Rosenberg, Michael AB -

BACKGROUND: 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.

VL - 6 IS - 2 ER - TY - JOUR T1 - {Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis JF - Genome Biol Y1 - 2022 A1 - Kanoni, S. A1 - Graham, S. E. A1 - Wang, Y. A1 - Surakka, I. A1 - Ramdas, S. A1 - Zhu, X. A1 - Clarke, S. L. A1 - Bhatti, K. F. A1 - Vedantam, S. A1 - Winkler, T. W. A1 - Locke, A. E. A1 - Marouli, E. A1 - Zajac, G. J. M. A1 - Wu, K. H. A1 - Ntalla, I. A1 - Hui, Q. A1 - Klarin, D. A1 - Hilliard, A. T. A1 - Wang, Z. A1 - Xue, C. A1 - Thorleifsson, G. A1 - Helgadottir, A. A1 - Gudbjartsson, D. F. A1 - Holm, H. A1 - Olafsson, I. A1 - Hwang, M. Y. A1 - Han, S. A1 - Akiyama, M. A1 - Sakaue, S. A1 - Terao, C. A1 - Kanai, M. A1 - Zhou, W. A1 - Brumpton, B. M. A1 - Rasheed, H. A1 - Havulinna, A. S. A1 - Veturi, Y. A1 - Pacheco, J. A. A1 - Rosenthal, E. A. A1 - Lingren, T. A1 - Feng, Q. A1 - Kullo, I. J. A1 - Narita, A. A1 - Takayama, J. A1 - Martin, H. C. A1 - Hunt, K. A. A1 - Trivedi, B. A1 - Haessler, J. A1 - Giulianini, F. A1 - Bradford, Y. A1 - Miller, J. E. A1 - Campbell, A. A1 - Lin, K. A1 - Millwood, I. Y. A1 - Rasheed, A. A1 - Hindy, G. A1 - Faul, J. D. A1 - Zhao, W. A1 - Weir, D. R. A1 - Turman, C. A1 - Huang, H. A1 - Graff, M. A1 - Choudhury, A. A1 - Sengupta, D. A1 - Mahajan, A. A1 - Brown, M. R. A1 - Zhang, W. A1 - Yu, K. A1 - Schmidt, E. M. A1 - Pandit, A. A1 - Gustafsson, S. A1 - Yin, X. A1 - Luan, J. A1 - Zhao, J. H. A1 - Matsuda, F. A1 - Jang, H. M. A1 - Yoon, K. A1 - Medina-Gomez, C. A1 - Pitsillides, A. A1 - Hottenga, J. J. A1 - Wood, A. R. A1 - Ji, Y. A1 - Gao, Z. A1 - Haworth, S. A1 - Yousri, N. A. A1 - Mitchell, R. E. A1 - Chai, J. F. A1 - Aadahl, M. A1 - Bjerregaard, A. A. A1 - Yao, J. A1 - Manichaikul, A. A1 - Hwu, C. M. A1 - Hung, Y. J. A1 - Warren, H. R. A1 - Ramirez, J. A1 - Bork-Jensen, J. A1 - rhus, L. L. A1 - Goel, A. A1 - Sabater-Lleal, M. A1 - Noordam, R. A1 - Mauro, P. A1 - Matteo, F. A1 - McDaid, A. F. A1 - Marques-Vidal, P. A1 - Wielscher, M. A1 - Trompet, S. A1 - Sattar, N. A1 - llehave, L. T. A1 - Munz, M. A1 - Zeng, L. A1 - Huang, J. A1 - Yang, B. A1 - Poveda, A. A1 - Kurbasic, A. A1 - Lamina, C. A1 - Forer, L. A1 - Scholz, M. A1 - Galesloot, T. E. A1 - Bradfield, J. P. A1 - Ruotsalainen, S. E. A1 - Daw, E. A1 - Zmuda, J. M. A1 - Mitchell, J. S. A1 - Fuchsberger, C. A1 - Christensen, H. A1 - Brody, J. A. A1 - Vazquez-Moreno, M. A1 - Feitosa, M. F. A1 - Wojczynski, M. K. A1 - Wang, Z. A1 - Preuss, M. H. A1 - Mangino, M. A1 - Christofidou, P. A1 - Verweij, N. A1 - Benjamins, J. W. A1 - Engmann, J. A1 - Tsao, N. L. A1 - Verma, A. A1 - Slieker, R. C. A1 - Lo, K. S. A1 - Zilhao, N. R. A1 - Le, P. A1 - Kleber, M. E. A1 - Delgado, G. E. A1 - Huo, S. A1 - Ikeda, D. D. A1 - Iha, H. A1 - Yang, J. A1 - Liu, J. A1 - Demirkan, A. A1 - Leonard, H. L. A1 - Marten, J. A1 - Frank, M. A1 - Schmidt, B. A1 - Smyth, L. J. A1 - adas-Garre, M. A1 - Wang, C. A1 - Nakatochi, M. A1 - Wong, A. A1 - nen, N. A1 - Sim, X. A1 - Xia, R. A1 - Huerta-Chagoya, A. A1 - Fernandez-Lopez, J. C. A1 - Lyssenko, V. A1 - Nongmaithem, S. S. A1 - Bayyana, S. A1 - Stringham, H. M. A1 - Irvin, M. R. A1 - Oldmeadow, C. A1 - Kim, H. N. A1 - Ryu, S. A1 - Timmers, P. R. H. J. A1 - Arbeeva, L. A1 - Dorajoo, R. A1 - Lange, L. A. A1 - Prasad, G. A1 - s-Motta, L. A1 - Pauper, M. A1 - Long, J. A1 - Li, X. A1 - Theusch, E. A1 - Takeuchi, F. A1 - Spracklen, C. N. A1 - Loukola, A. A1 - Bollepalli, S. A1 - Warner, S. C. A1 - Wang, Y. X. A1 - Wei, W. B. A1 - Nutile, T. A1 - Ruggiero, D. A1 - Sung, Y. J. A1 - Chen, S. A1 - Liu, F. A1 - Yang, J. A1 - Kentistou, K. A. A1 - Banas, B. A1 - Nardone, G. G. A1 - Meidtner, K. A1 - Bielak, L. F. A1 - Smith, J. A. A1 - Hebbar, P. A1 - Farmaki, A. E. A1 - Hofer, E. A1 - Lin, M. A1 - Concas, M. P. A1 - Vaccargiu, S. A1 - van der Most, P. J. A1 - nen, N. A1 - Cade, B. E. A1 - van der Laan, S. W. A1 - Chitrala, K. N. A1 - Weiss, S. A1 - Bentley, A. R. A1 - Doumatey, A. P. A1 - Adeyemo, A. A. A1 - Lee, J. Y. A1 - Petersen, E. R. B. A1 - Nielsen, A. A. A1 - Choi, H. S. A1 - Nethander, M. A1 - Freitag-Wolf, S. A1 - Southam, L. A1 - Rayner, N. W. A1 - Wang, C. A. A1 - Lin, S. Y. A1 - Wang, J. S. A1 - Couture, C. A1 - inen, L. P. A1 - Nikus, K. A1 - Cuellar-Partida, G. A1 - Vestergaard, H. A1 - Hidalgo, B. A1 - Giannakopoulou, O. A1 - Cai, Q. A1 - Obura, M. O. A1 - van Setten, J. A1 - Li, X. A1 - Liang, J. A1 - Tang, H. A1 - Terzikhan, N. A1 - Shin, J. H. A1 - Jackson, R. D. A1 - Reiner, A. P. A1 - Martin, L. W. A1 - Chen, Z. A1 - Li, L. A1 - Kawaguchi, T. A1 - Thiery, J. A1 - Bis, J. C. A1 - Launer, L. J. A1 - Li, H. A1 - Nalls, M. A. A1 - Raitakari, O. T. A1 - Ichihara, S. A1 - Wild, S. H. A1 - Nelson, C. P. A1 - Campbell, H. A1 - ger, S. A1 - Nabika, T. A1 - Al-Mulla, F. A1 - Niinikoski, H. A1 - Braund, P. S. A1 - Kolcic, I. A1 - Kovacs, P. A1 - Giardoglou, T. A1 - Katsuya, T. A1 - de Kleijn, D. A1 - de Borst, G. J. A1 - Kim, E. K. A1 - Adams, H. H. H. A1 - Ikram, M. A. A1 - Zhu, X. A1 - Asselbergs, F. W. A1 - Kraaijeveld, A. O. A1 - Beulens, J. W. J. A1 - Shu, X. O. A1 - Rallidis, L. S. A1 - Pedersen, O. A1 - Hansen, T. A1 - Mitchell, P. A1 - Hewitt, A. W. A1 - nen, M. A1 - russe, L. A1 - Bouchard, C. A1 - njes, A. A1 - Chen, Y. I. A1 - Pennell, C. E. A1 - Mori, T. A. A1 - Lieb, W. A1 - Franke, A. A1 - Ohlsson, C. A1 - m, D. A1 - Cho, Y. S. A1 - Lee, H. A1 - Yuan, J. M. A1 - Koh, W. P. A1 - Rhee, S. Y. A1 - Woo, J. T. A1 - Heid, I. M. A1 - Stark, K. J. A1 - Zimmermann, M. E. A1 - lzke, H. A1 - Homuth, G. A1 - Evans, M. K. A1 - Zonderman, A. B. A1 - Polasek, O. A1 - Pasterkamp, G. A1 - Hoefer, I. E. A1 - Redline, S. A1 - Pahkala, K. A1 - Oldehinkel, A. J. A1 - Snieder, H. A1 - Biino, G. A1 - Schmidt, R. A1 - Schmidt, H. A1 - Bandinelli, S. A1 - Dedoussis, G. A1 - Thanaraj, T. A. A1 - Kardia, S. L. R. A1 - Peyser, P. A. A1 - Kato, N. A1 - Schulze, M. B. A1 - Girotto, G. A1 - ger, C. A. A1 - Jung, B. A1 - Joshi, P. K. A1 - Bennett, D. A. A1 - De Jager, P. L. A1 - Lu, X. A1 - Mamakou, V. A1 - Brown, M. A1 - Caulfield, M. J. A1 - Munroe, P. B. A1 - Guo, X. A1 - Ciullo, M. A1 - Jonas, J. B. A1 - Samani, N. J. A1 - Kaprio, J. A1 - Pajukanta, P. A1 - -Luna, T. A1 - Aguilar-Salinas, C. A. A1 - Adair, L. S. A1 - Bechayda, S. A. A1 - de Silva, H. J. A1 - Wickremasinghe, A. R. A1 - Krauss, R. M. A1 - Wu, J. Y. A1 - Zheng, W. A1 - Hollander, A. I. A1 - Bharadwaj, D. A1 - Correa, A. A1 - Wilson, J. G. A1 - Lind, L. A1 - Heng, C. K. A1 - Nelson, A. E. A1 - Golightly, Y. M. A1 - Wilson, J. F. A1 - Penninx, B. A1 - Kim, H. L. A1 - Attia, J. A1 - Scott, R. J. A1 - Rao, D. C. A1 - Arnett, D. K. A1 - Hunt, S. C. A1 - Walker, M. A1 - Koistinen, H. A. A1 - Chandak, G. R. A1 - Mercader, J. M. A1 - Costanzo, M. C. A1 - Jang, D. A1 - Burtt, N. P. A1 - Villalpando, C. G. A1 - Orozco, L. A1 - Fornage, M. A1 - Tai, E. A1 - van Dam, R. M. A1 - ki, T. A1 - Chaturvedi, N. A1 - Yokota, M. A1 - Liu, J. A1 - Reilly, D. F. A1 - McKnight, A. J. A1 - Kee, F. A1 - ckel, K. H. A1 - McCarthy, M. I. A1 - Palmer, C. N. A. A1 - Vitart, V. A1 - Hayward, C. A1 - Simonsick, E. A1 - van Duijn, C. M. A1 - Jin, Z. B. A1 - Qu, J. A1 - Hishigaki, H. A1 - Lin, X. A1 - rz, W. A1 - Gudnason, V. A1 - Tardif, J. C. A1 - Lettre, G. A1 - Hart, L. M. ' A1 - Elders, P. J. M. A1 - Damrauer, S. M. A1 - Kumari, M. A1 - Kivimaki, M. A1 - van der Harst, P. A1 - Spector, T. D. A1 - Loos, R. J. F. A1 - Province, M. A. A1 - Parra, E. J. A1 - Cruz, M. A1 - Psaty, B. M. A1 - Brandslund, I. A1 - Pramstaller, P. P. A1 - Rotimi, C. N. A1 - Christensen, K. A1 - Ripatti, S. A1 - n, E. A1 - Hakonarson, H. A1 - Grant, S. F. A. A1 - Kiemeney, L. A. L. M. A1 - de Graaf, J. A1 - Loeffler, M. A1 - Kronenberg, F. A1 - Gu, D. A1 - Erdmann, J. A1 - Schunkert, H. A1 - Franks, P. W. A1 - Linneberg, A. A1 - Jukema, J. W. A1 - Khera, A. V. A1 - ö, M. A1 - Jarvelin, M. R. A1 - Kutalik, Z. A1 - Francesco, C. A1 - Mook-Kanamori, D. O. A1 - van Dijk, K. W. A1 - Watkins, H. A1 - Strachan, D. P. A1 - Grarup, N. A1 - Sever, P. A1 - Poulter, N. A1 - Chuang, L. M. A1 - Rotter, J. I. A1 - Dantoft, T. M. A1 - Karpe, F. A1 - Neville, M. J. A1 - Timpson, N. J. A1 - Cheng, C. Y. A1 - Wong, T. Y. A1 - Khor, C. C. A1 - Li, H. A1 - Sabanayagam, C. A1 - Peters, A. A1 - Gieger, C. A1 - Hattersley, A. T. A1 - Pedersen, N. L. A1 - Magnusson, P. K. E. A1 - Boomsma, D. I. A1 - Willemsen, A. H. M. A1 - Cupples, L. A1 - van Meurs, J. B. J. A1 - Ghanbari, M. A1 - Gordon-Larsen, P. A1 - Huang, W. A1 - Kim, Y. J. A1 - Tabara, Y. A1 - Wareham, N. J. A1 - Langenberg, C. A1 - Zeggini, E. A1 - Kuusisto, J. A1 - Laakso, M. A1 - Ingelsson, E. A1 - Abecasis, G. A1 - Chambers, J. C. A1 - Kooner, J. S. A1 - de Vries, P. S. A1 - Morrison, A. C. A1 - Hazelhurst, S. A1 - Ramsay, M. A1 - North, K. E. A1 - Daviglus, M. A1 - Kraft, P. A1 - Martin, N. G. A1 - Whitfield, J. B. A1 - Abbas, S. A1 - Saleheen, D. A1 - Walters, R. G. A1 - Holmes, M. V. A1 - Black, C. A1 - Smith, B. H. A1 - Baras, A. A1 - Justice, A. E. A1 - Buring, J. E. A1 - Ridker, P. M. A1 - Chasman, D. I. A1 - Kooperberg, C. A1 - Tamiya, G. A1 - Yamamoto, M. A1 - van Heel, D. A. A1 - Trembath, R. C. A1 - Wei, W. Q. A1 - Jarvik, G. P. A1 - Namjou, B. A1 - Hayes, M. G. A1 - Ritchie, M. D. A1 - Jousilahti, P. A1 - Salomaa, V. A1 - Hveem, K. A1 - svold, B. O. A1 - Kubo, M. A1 - Kamatani, Y. A1 - Okada, Y. A1 - Murakami, Y. A1 - Kim, B. J. A1 - Thorsteinsdottir, U. A1 - Stefansson, K. A1 - Zhang, J. A1 - Chen, Y. A1 - Ho, Y. L. A1 - Lynch, J. A. A1 - Rader, D. J. A1 - Tsao, P. S. A1 - Chang, K. M. A1 - Cho, K. A1 - O'Donnell, C. J. A1 - Gaziano, J. M. A1 - Wilson, P. W. F. A1 - Frayling, T. M. A1 - Hirschhorn, J. N. A1 - Kathiresan, S. A1 - Mohlke, K. L. A1 - Sun, Y. V. A1 - Morris, A. P. A1 - Boehnke, M. A1 - Brown, C. D. A1 - Natarajan, P. A1 - Deloukas, P. A1 - Willer, C. J. A1 - Assimes, T. L. A1 - Peloso, G. M. AB - Genetic 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. VL - 23 ER - TY - JOUR T1 - Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. JF - Hypertension Y1 - 2022 A1 - Kelly, Tanika N A1 - Sun, Xiao A1 - He, Karen Y A1 - Brown, Michael R A1 - Taliun, Sarah A Gagliano A1 - Hellwege, Jacklyn N A1 - Irvin, Marguerite R A1 - Mi, Xuenan A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - de Vries, Paul S A1 - Gao, Yan A1 - Moscati, Arden A1 - Nadkarni, Girish N A1 - Yanek, Lisa R A1 - Elfassy, Tali A1 - Smith, Jennifer A A1 - Chung, Ren-Hua A1 - Beitelshees, Amber L A1 - Patki, Amit A1 - Aslibekyan, Stella A1 - Blobner, Brandon M A1 - Peralta, Juan M A1 - Assimes, Themistocles L A1 - Palmas, Walter R A1 - Liu, Chunyu A1 - Bress, Adam P A1 - Huang, Zhijie A1 - Becker, Lewis C A1 - Hwa, Chii-Min A1 - O'Connell, Jeffrey R A1 - Carlson, Jenna C A1 - Warren, Helen R A1 - Das, Sayantan A1 - Giri, Ayush A1 - Martin, Lisa W A1 - Craig Johnson, W A1 - Fox, Ervin R A1 - Bottinger, Erwin P A1 - Razavi, Alexander C A1 - Vaidya, Dhananjay A1 - Chuang, Lee-Ming A1 - Chang, Yen-Pei C A1 - Naseri, Take A1 - Jain, Deepti A1 - Kang, Hyun Min A1 - Hung, Adriana M A1 - Srinivasasainagendra, Vinodh A1 - Snively, Beverly M A1 - Gu, Dongfeng A1 - Montasser, May E A1 - Reupena, Muagututi'a Sefuiva A1 - Heavner, Benjamin D A1 - LeFaive, Jonathon A1 - Hixson, James E A1 - Rice, Kenneth M A1 - Wang, Fei Fei A1 - Nielsen, Jonas B A1 - Huang, Jianfeng A1 - Khan, Alyna T A1 - Zhou, Wei A1 - Nierenberg, Jovia L A1 - Laurie, Cathy C A1 - Armstrong, Nicole D A1 - Shi, Mengyao A1 - Pan, Yang A1 - Stilp, Adrienne M A1 - Emery, Leslie A1 - Wong, Quenna A1 - Hawley, Nicola L A1 - Minster, Ryan L A1 - Curran, Joanne E A1 - Munroe, Patricia B A1 - Weeks, Daniel E A1 - North, Kari E A1 - Tracy, Russell P A1 - Kenny, Eimear E A1 - Shimbo, Daichi A1 - Chakravarti, Aravinda A1 - Rich, Stephen S A1 - Reiner, Alex P A1 - Blangero, John A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Rao, Dabeeru C A1 - Ida Chen, Yii-Der A1 - Kardia, Sharon L R A1 - Kaplan, Robert C A1 - Mathias, Rasika A A1 - He, Jiang A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Loos, Ruth J F A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Edwards, Todd L A1 - Abecasis, Goncalo R A1 - Zhu, Xiaofeng A1 - Levy, Daniel A1 - Arnett, Donna K A1 - Morrison, Alanna C AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults. JF - JAMA Netw Open Y1 - 2022 A1 - Shivakoti, Rupak A1 - Biggs, Mary L A1 - Djoussé, Luc A1 - Durda, Peter Jon A1 - Kizer, Jorge R A1 - Psaty, Bruce A1 - Reiner, Alex P A1 - Tracy, Russell P A1 - Siscovick, David A1 - Mukamal, Kenneth J KW - Adult KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Dietary Fiber KW - Female KW - Humans KW - Inflammation KW - Middle Aged KW - Risk Factors AB -

Importance: 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.

VL - 5 IS - 3 ER - TY - JOUR T1 - Integrative analysis of clinical and epigenetic biomarkers of mortality. JF - Aging Cell Y1 - 2022 A1 - Huan, Tianxiao A1 - Nguyen, Steve A1 - Colicino, Elena A1 - Ochoa-Rosales, Carolina A1 - Hill, W David A1 - Brody, Jennifer A A1 - Soerensen, Mette A1 - Zhang, Yan A1 - Baldassari, Antoine A1 - Elhadad, Mohamed Ahmed A1 - Toshiko, Tanaka A1 - Zheng, Yinan A1 - Domingo-Relloso, Arce A1 - Lee, Dong Heon A1 - Ma, Jiantao A1 - Yao, Chen A1 - Liu, Chunyu A1 - Hwang, Shih-Jen A1 - Joehanes, Roby A1 - Fornage, Myriam A1 - Bressler, Jan A1 - van Meurs, Joyce B J A1 - Debrabant, Birgit A1 - Mengel-From, Jonas A1 - Hjelmborg, Jacob A1 - Christensen, Kaare A1 - Vokonas, Pantel A1 - Schwartz, Joel A1 - Gahrib, Sina A A1 - Sotoodehnia, Nona A1 - Sitlani, Colleen M A1 - Kunze, Sonja A1 - Gieger, Christian A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Qu, Yishu A1 - Greenland, Philip A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Bandinelli, Stefania A1 - Voortman, Trudy A1 - Hermann, Brenner A1 - Baccarelli, Andrea A1 - Whitsel, Eric A1 - Pankow, James S A1 - Levy, Daniel KW - Biomarkers KW - Cardiovascular Diseases KW - DNA Methylation KW - Epigenesis, Genetic KW - Epigenomics KW - Humans KW - Male KW - Neoplasms AB -

DNA 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.

VL - 21 IS - 6 ER - TY - JOUR T1 - Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. JF - Nat Med Y1 - 2022 A1 - Tcheandjieu, Catherine A1 - Zhu, Xiang A1 - Hilliard, Austin T A1 - Clarke, Shoa L A1 - Napolioni, Valerio A1 - Ma, Shining A1 - Lee, Kyung Min A1 - Fang, Huaying A1 - Chen, Fei A1 - Lu, Yingchang A1 - Tsao, Noah L A1 - Raghavan, Sridharan A1 - Koyama, Satoshi A1 - Gorman, Bryan R A1 - Vujkovic, Marijana A1 - Klarin, Derek A1 - Levin, Michael G A1 - Sinnott-Armstrong, Nasa A1 - Wojcik, Genevieve L A1 - Plomondon, Mary E A1 - Maddox, Thomas M A1 - Waldo, Stephen W A1 - Bick, Alexander G A1 - Pyarajan, Saiju A1 - Huang, Jie A1 - Song, Rebecca A1 - Ho, Yuk-Lam A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - Haessler, Jeffrey A1 - Loos, Ruth J F A1 - Do, Ron A1 - Verbanck, Marie A1 - Chaudhary, Kumardeep A1 - North, Kari E A1 - Avery, Christy L A1 - Graff, Mariaelisa A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Wilkens, Lynne R A1 - Bis, Joshua C A1 - Leonard, Hampton A1 - Shen, Botong A1 - Lange, Leslie A A1 - Giri, Ayush A1 - Dikilitas, Ozan A1 - Kullo, Iftikhar J A1 - Stanaway, Ian B A1 - Jarvik, Gail P A1 - Gordon, Adam S A1 - Hebbring, Scott A1 - Namjou, Bahram A1 - Kaufman, Kenneth M A1 - Ito, Kaoru A1 - Ishigaki, Kazuyoshi A1 - Kamatani, Yoichiro A1 - Verma, Shefali S A1 - Ritchie, Marylyn D A1 - Kember, Rachel L A1 - Baras, Aris A1 - Lotta, Luca A A1 - Kathiresan, Sekar A1 - Hauser, Elizabeth R A1 - Miller, Donald R A1 - Lee, Jennifer S A1 - Saleheen, Danish A1 - Reaven, Peter D A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Natarajan, Pradeep A1 - Huffman, Jennifer E A1 - Voight, Benjamin F A1 - Rader, Daniel J A1 - Chang, Kyong-Mi A1 - Lynch, Julie A A1 - Damrauer, Scott M A1 - Wilson, Peter W F A1 - Tang, Hua A1 - Sun, Yan V A1 - Tsao, Philip S A1 - O'Donnell, Christopher J A1 - Assimes, Themistocles L KW - Coronary Artery Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We 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.

VL - 28 IS - 8 ER - TY - JOUR T1 - Monocyte subsets, T cell activation profiles, and stroke in men and women: The Multi-Ethnic Study of Atherosclerosis and Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2022 A1 - Feinstein, Matthew J A1 - Bůzková, Petra A1 - Olson, Nels C A1 - Doyle, Margaret F A1 - Sitlani, Colleen M A1 - Fohner, Alison E A1 - Huber, Sally A A1 - Floyd, James A1 - Sinha, Arjun A1 - Thorp, Edward B A1 - Landay, Alan A1 - Freiberg, Matthew S A1 - Longstreth, William T A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Delaney, Joseph Ac KW - Atherosclerosis KW - CD4-Positive T-Lymphocytes KW - CD8-Positive T-Lymphocytes KW - Cytokines KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Inflammation KW - Interleukin-4 KW - Ischemic Stroke KW - Lymphocyte Activation KW - Male KW - Monocytes KW - Stroke KW - T-Lymphocyte Subsets AB -

BACKGROUND 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.

VL - 351 ER - TY - JOUR T1 - Monogenic and Polygenic Contributions to QTc Prolongation in the Population. JF - Circulation Y1 - 2022 A1 - Nauffal, Victor A1 - Morrill, Valerie N A1 - Jurgens, Sean J A1 - Choi, Seung Hoan A1 - Hall, Amelia W A1 - Weng, Lu-Chen A1 - Halford, Jennifer L A1 - Austin-Tse, Christina A1 - Haggerty, Christopher M A1 - Harris, Stephanie L A1 - Wong, Eugene K A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Boerwinkle, Eric A1 - Min, Yuan-I A1 - Correa, Adolfo A1 - Fornwalt, Brandon K A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Rice, Kenneth M A1 - Gupta, Namrata A1 - Blackwell, Thomas W A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Post, Wendy S A1 - Redline, Susan A1 - Rehm, Heidi L A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T A1 - Lubitz, Steven A AB -

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.

ER - TY - JOUR T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. JF - Nat Genet Y1 - 2022 A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Zhang, Weihua A1 - Ng, Maggie C Y A1 - Petty, Lauren E A1 - Kitajima, Hidetoshi A1 - Yu, Grace Z A1 - Rüeger, Sina A1 - Speidel, Leo A1 - Kim, Young Jin A1 - Horikoshi, Momoko A1 - Mercader, Josep M A1 - Taliun, Daniel A1 - Moon, Sanghoon A1 - Kwak, Soo-Heon A1 - Robertson, Neil R A1 - Rayner, Nigel W A1 - Loh, Marie A1 - Kim, Bong-Jo A1 - Chiou, Joshua A1 - Miguel-Escalada, Irene A1 - Della Briotta Parolo, Pietro A1 - Lin, Kuang A1 - Bragg, Fiona A1 - Preuss, Michael H A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Guo, Xiuqing A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Scott, Robert A A1 - Lee, Jung-Jin A1 - Huerta-Chagoya, Alicia A1 - Graff, Mariaelisa A1 - Chai, Jin-Fang A1 - Parra, Esteban J A1 - Yao, Jie A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Steinthorsdottir, Valgerdur A1 - Cook, James P A1 - Kals, Mart A1 - Grarup, Niels A1 - Schmidt, Ellen M A1 - Pan, Ian A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Ahmad, Meraj A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Lecoeur, Cécile A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Jensen, Richard A A1 - Tajuddin, Salman A1 - Kabagambe, Edmond K A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Flanagan, Jack A1 - Abaitua, Fernando A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Akiyama, Masato A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bian, Zheng A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Brummett, Chad M A1 - Buchanan, Thomas A A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Fuchsberger, Christian A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Goodarzi, Mark O A1 - Gordon-Larsen, Penny A1 - Gorkin, David A1 - Gross, Myron A1 - Guo, Yu A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Kamatani, Yoichiro A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kohara, Katsuhiko A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lyssenko, Valeriya A1 - Mamakou, Vasiliki A1 - Mani, K Radha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nadkarni, Girish N A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Nongmaithem, Suraj S A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Preissl, Sebastian A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Kathryn A1 - Sabanayagam, Charumathi A1 - Sander, Maike A1 - Sandow, Kevin A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Schurmann, Claudia A1 - Shahriar, Mohammad A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shriner, Daniel A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Suzuki, Ken A1 - Takahashi, Atsushi A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Torres, Jason M A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Vujkovic, Marijana A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Whitsel, Eric A A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamauchi, Toshimasa A1 - Yengo, Loic A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Hanis, Craig L A1 - Peyser, Patricia A A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Zeggini, Eleftheria A1 - Yokota, Mitsuhiro A1 - Rich, Stephen S A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Engert, James C A1 - Chen, Yii-Der Ida A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Kardia, Sharon L R A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Groop, Leif A1 - Mook-Kanamori, Dennis O A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Bottinger, Erwin P A1 - Dehghan, Abbas A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Palmer, Colin N A A1 - Liu, Simin A1 - Abecasis, Goncalo A1 - Kooner, Jaspal S A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A A1 - Florez, Jose C A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Mägi, Reedik A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Maeda, Shiro A1 - Kadowaki, Takashi A1 - Lee, Juyoung A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Myers, Simon R A1 - Ferrer, Jorge A1 - Gaulton, Kyle J A1 - Meigs, James B A1 - Mohlke, Karen L A1 - Gloyn, Anna L A1 - Bowden, Donald W A1 - Below, Jennifer E A1 - Chambers, John C A1 - Sim, Xueling A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - McCarthy, Mark I A1 - Morris, Andrew P KW - Diabetes Mellitus, Type 2 KW - Ethnicity KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We 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.

VL - 54 IS - 5 ER - TY - JOUR T1 - A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. JF - Nat Commun Y1 - 2022 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Kelly, Tanika N A1 - Elfassy, Tali A1 - Wiggins, Kerri L A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Taylor, Kent D A1 - Lin, Henry J A1 - Haessler, Jeffrey A1 - Gao, Yan A1 - Shimbo, Daichi A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Feofanova, Elena V A1 - Smit, Roelof A J A1 - Wang, Zhe A1 - Hwang, Shih-Jen A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Lloyd-Jones, Donald M A1 - Rich, Stephen S A1 - Loos, Ruth J F A1 - Redline, Susan A1 - Correa, Adolfo A1 - Kooperberg, Charles A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Morrison, Alanna C A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Sofer, Tamar KW - Adult KW - Diabetes Mellitus, Type 2 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Multifactorial Inheritance KW - Prevalence KW - Risk Factors AB -

In 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.

VL - 13 IS - 1 ER - TY - JOUR T1 - Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease. JF - Diabetes Y1 - 2022 A1 - Liu, Jiahao A1 - Nair, Viji A1 - Zhao, Yi-Yang A1 - Chang, Dong-Yuan A1 - Limonte, Christine A1 - Bansal, Nisha A1 - Fermin, Damian A1 - Eichinger, Felix A1 - Tanner, Emily C A1 - Bellovich, Keith A A1 - Steigerwalt, Susan A1 - Bhat, Zeenat A1 - Hawkins, Jennifer J A1 - Subramanian, Lalita A1 - Rosas, Sylvia E A1 - Sedor, John R A1 - Vasquez, Miguel A A1 - Waikar, Sushrut S A1 - Bitzer, Markus A1 - Pennathur, Subramaniam A1 - Brosius, Frank C A1 - de Boer, Ian A1 - Chen, Min A1 - Kretzler, Matthias A1 - Ju, Wenjun KW - Angiopoietin-1 KW - Angiopoietin-2 KW - Angiopoietins KW - Biomarkers KW - Cohort Studies KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Disease Progression KW - Endothelial Cells KW - Humans KW - Kidney Failure, Chronic KW - Receptor, TIE-2 KW - Signal Transduction AB -

Diabetic 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.

VL - 71 IS - 12 ER - TY - JOUR T1 - New insights into the genetic etiology of Alzheimer's disease and related dementias. JF - Nat Genet Y1 - 2022 A1 - Bellenguez, Céline A1 - Küçükali, Fahri A1 - Jansen, Iris E A1 - Kleineidam, Luca A1 - Moreno-Grau, Sonia A1 - Amin, Najaf A1 - Naj, Adam C A1 - Campos-Martin, Rafael A1 - Grenier-Boley, Benjamin A1 - Andrade, Victor A1 - Holmans, Peter A A1 - Boland, Anne A1 - Damotte, Vincent A1 - van der Lee, Sven J A1 - Costa, Marcos R A1 - Kuulasmaa, Teemu A1 - Yang, Qiong A1 - de Rojas, Itziar A1 - Bis, Joshua C A1 - Yaqub, Amber A1 - Prokic, Ivana A1 - Chapuis, Julien A1 - Ahmad, Shahzad A1 - Giedraitis, Vilmantas A1 - Aarsland, Dag A1 - Garcia-Gonzalez, Pablo A1 - Abdelnour, Carla A1 - Alarcón-Martín, Emilio A1 - Alcolea, Daniel A1 - Alegret, Montserrat A1 - Alvarez, Ignacio A1 - Alvarez, Victoria A1 - Armstrong, Nicola J A1 - Tsolaki, Anthoula A1 - Antunez, Carmen A1 - Appollonio, Ildebrando A1 - Arcaro, Marina A1 - Archetti, Silvana A1 - Pastor, Alfonso Arias A1 - Arosio, Beatrice A1 - Athanasiu, Lavinia A1 - Bailly, Henri A1 - Banaj, Nerisa A1 - Baquero, Miquel A1 - Barral, Sandra A1 - Beiser, Alexa A1 - Pastor, Ana Belén A1 - Below, Jennifer E A1 - Benchek, Penelope A1 - Benussi, Luisa A1 - Berr, Claudine A1 - Besse, Céline A1 - Bessi, Valentina A1 - Binetti, Giuliano A1 - Bizarro, Alessandra A1 - Blesa, Rafael A1 - Boada, Merce A1 - Boerwinkle, Eric A1 - Borroni, Barbara A1 - Boschi, Silvia A1 - Bossù, Paola A1 - Bråthen, Geir A1 - Bressler, Jan A1 - Bresner, Catherine A1 - Brodaty, Henry A1 - Brookes, Keeley J A1 - Brusco, Luis Ignacio A1 - Buiza-Rueda, Dolores A1 - Bûrger, Katharina A1 - Burholt, Vanessa A1 - Bush, William S A1 - Calero, Miguel A1 - Cantwell, Laura B A1 - Chene, Geneviève A1 - Chung, Jaeyoon A1 - Cuccaro, Michael L A1 - Carracedo, Angel A1 - Cecchetti, Roberta A1 - Cervera-Carles, Laura A1 - Charbonnier, Camille A1 - Chen, Hung-Hsin A1 - Chillotti, Caterina A1 - Ciccone, Simona A1 - Claassen, Jurgen A H R A1 - Clark, Christopher A1 - Conti, Elisa A1 - Corma-Gómez, Anaïs A1 - Costantini, Emanuele A1 - Custodero, Carlo A1 - Daian, Delphine A1 - Dalmasso, Maria Carolina A1 - Daniele, Antonio A1 - Dardiotis, Efthimios A1 - Dartigues, Jean-François A1 - de Deyn, Peter Paul A1 - de Paiva Lopes, Katia A1 - de Witte, Lot D A1 - Debette, Stephanie A1 - Deckert, Jürgen A1 - Del Ser, Teodoro A1 - Denning, Nicola A1 - DeStefano, Anita A1 - Dichgans, Martin A1 - Diehl-Schmid, Janine A1 - Diez-Fairen, Monica A1 - Rossi, Paolo Dionigi A1 - Djurovic, Srdjan A1 - Duron, Emmanuelle A1 - Düzel, Emrah A1 - Dufouil, Carole A1 - Eiriksdottir, Gudny A1 - Engelborghs, Sebastiaan A1 - Escott-Price, Valentina A1 - Espinosa, Ana A1 - Ewers, Michael A1 - Faber, Kelley M A1 - Fabrizio, Tagliavini A1 - Nielsen, Sune Fallgaard A1 - Fardo, David W A1 - Farotti, Lucia A1 - Fenoglio, Chiara A1 - Fernández-Fuertes, Marta A1 - Ferrari, Raffaele A1 - Ferreira, Catarina B A1 - Ferri, Evelyn A1 - Fin, Bertrand A1 - Fischer, Peter A1 - Fladby, Tormod A1 - Fließbach, Klaus A1 - Fongang, Bernard A1 - Fornage, Myriam A1 - Fortea, Juan A1 - Foroud, Tatiana M A1 - Fostinelli, Silvia A1 - Fox, Nick C A1 - Franco-Macías, Emlio A1 - Bullido, María J A1 - Frank-García, Ana A1 - Froelich, Lutz A1 - Fulton-Howard, Brian A1 - Galimberti, Daniela A1 - García-Alberca, Jose Maria A1 - Garcia-Gonzalez, Pablo A1 - Garcia-Madrona, Sebastian A1 - Garcia-Ribas, Guillermo A1 - Ghidoni, Roberta A1 - Giegling, Ina A1 - Giorgio, Giaccone A1 - Goate, Alison M A1 - Goldhardt, Oliver A1 - Gomez-Fonseca, Duber A1 - González-Perez, Antonio A1 - Graff, Caroline A1 - Grande, Giulia A1 - Green, Emma A1 - Grimmer, Timo A1 - Grünblatt, Edna A1 - Grunin, Michelle A1 - Gudnason, Vilmundur A1 - Guetta-Baranes, Tamar A1 - Haapasalo, Annakaisa A1 - Hadjigeorgiou, Georgios A1 - Haines, Jonathan L A1 - Hamilton-Nelson, Kara L A1 - Hampel, Harald A1 - Hanon, Olivier A1 - Hardy, John A1 - Hartmann, Annette M A1 - Hausner, Lucrezia A1 - Harwood, Janet A1 - Heilmann-Heimbach, Stefanie A1 - Helisalmi, Seppo A1 - Heneka, Michael T A1 - Hernandez, Isabel A1 - Herrmann, Martin J A1 - Hoffmann, Per A1 - Holmes, Clive A1 - Holstege, Henne A1 - Vilas, Raquel Huerto A1 - Hulsman, Marc A1 - Humphrey, Jack A1 - Biessels, Geert Jan A1 - Jian, Xueqiu A1 - Johansson, Charlotte A1 - Jun, Gyungah R A1 - Kastumata, Yuriko A1 - Kauwe, John A1 - Kehoe, Patrick G A1 - Kilander, Lena A1 - Ståhlbom, Anne Kinhult A1 - Kivipelto, Miia A1 - Koivisto, Anne A1 - Kornhuber, Johannes A1 - Kosmidis, Mary H A1 - Kukull, Walter A A1 - Kuksa, Pavel P A1 - Kunkle, Brian W A1 - Kuzma, Amanda B A1 - Lage, Carmen A1 - Laukka, Erika J A1 - Launer, Lenore A1 - Lauria, Alessandra A1 - Lee, Chien-Yueh A1 - Lehtisalo, Jenni A1 - Lerch, Ondrej A1 - Lleo, Alberto A1 - Longstreth, William A1 - Lopez, Oscar A1 - de Munain, Adolfo Lopez A1 - Love, Seth A1 - Löwemark, Malin A1 - Luckcuck, Lauren A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Macías, Juan A1 - MacLeod, Catherine A A1 - Maier, Wolfgang A1 - Mangialasche, Francesca A1 - Spallazzi, Marco A1 - Marquié, Marta A1 - Marshall, Rachel A1 - Martin, Eden R A1 - Montes, Angel Martín A1 - Rodríguez, Carmen Martínez A1 - Masullo, Carlo A1 - Mayeux, Richard A1 - Mead, Simon A1 - Mecocci, Patrizia A1 - Medina, Miguel A1 - Meggy, Alun A1 - Mehrabian, Shima A1 - Mendoza, Silvia A1 - Menéndez-González, Manuel A1 - Mir, Pablo A1 - Moebus, Susanne A1 - Mol, Merel A1 - Molina-Porcel, Laura A1 - Montrreal, Laura A1 - Morelli, Laura A1 - Moreno, Fermin A1 - Morgan, Kevin A1 - Mosley, Thomas A1 - Nöthen, Markus M A1 - Muchnik, Carolina A1 - Mukherjee, Shubhabrata A1 - Nacmias, Benedetta A1 - Ngandu, Tiia A1 - Nicolas, Gaël A1 - Nordestgaard, Børge G A1 - Olaso, Robert A1 - Orellana, Adelina A1 - Orsini, Michela A1 - Ortega, Gemma A1 - Padovani, Alessandro A1 - Paolo, Caffarra A1 - Papenberg, Goran A1 - Parnetti, Lucilla A1 - Pasquier, Florence A1 - Pastor, Pau A1 - Peloso, Gina A1 - Pérez-Cordón, Alba A1 - Pérez-Tur, Jordi A1 - Pericard, Pierre A1 - Peters, Oliver A1 - Pijnenburg, Yolande A L A1 - Pineda, Juan A A1 - Piñol-Ripoll, Gerard A1 - Pisanu, Claudia A1 - Polak, Thomas A1 - Popp, Julius A1 - Posthuma, Danielle A1 - Priller, Josef A1 - Puerta, Raquel A1 - Quenez, Olivier A1 - Quintela, Inés A1 - Thomassen, Jesper Qvist A1 - Rábano, Alberto A1 - Rainero, Innocenzo A1 - Rajabli, Farid A1 - Ramakers, Inez A1 - Real, Luis M A1 - Reinders, Marcel J T A1 - Reitz, Christiane A1 - Reyes-Dumeyer, Dolly A1 - Ridge, Perry A1 - Riedel-Heller, Steffi A1 - Riederer, Peter A1 - Roberto, Natalia A1 - Rodriguez-Rodriguez, Eloy A1 - Rongve, Arvid A1 - Allende, Irene Rosas A1 - Rosende-Roca, Maitée A1 - Royo, Jose Luis A1 - Rubino, Elisa A1 - Rujescu, Dan A1 - Sáez, María Eugenia A1 - Sakka, Paraskevi A1 - Saltvedt, Ingvild A1 - Sanabria, Ángela A1 - Sánchez-Arjona, María Bernal A1 - Sanchez-Garcia, Florentino A1 - Juan, Pascual Sánchez A1 - Sánchez-Valle, Raquel A1 - Sando, Sigrid B A1 - Sarnowski, Chloe A1 - Satizabal, Claudia L A1 - Scamosci, Michela A1 - Scarmeas, Nikolaos A1 - Scarpini, Elio A1 - Scheltens, Philip A1 - Scherbaum, Norbert A1 - Scherer, Martin A1 - Schmid, Matthias A1 - Schneider, Anja A1 - Schott, Jonathan M A1 - Selbæk, Geir A1 - Seripa, Davide A1 - Serrano, Manuel A1 - Sha, Jin A1 - Shadrin, Alexey A A1 - Skrobot, Olivia A1 - Slifer, Susan A1 - Snijders, Gijsje J L A1 - Soininen, Hilkka A1 - Solfrizzi, Vincenzo A1 - Solomon, Alina A1 - Song, Yeunjoo A1 - Sorbi, Sandro A1 - Sotolongo-Grau, Oscar A1 - Spalletta, Gianfranco A1 - Spottke, Annika A1 - Squassina, Alessio A1 - Stordal, Eystein A1 - Tartan, Juan Pablo A1 - Tarraga, Lluis A1 - Tesí, Niccolo A1 - Thalamuthu, Anbupalam A1 - Thomas, Tegos A1 - Tosto, Giuseppe A1 - Traykov, Latchezar A1 - Tremolizzo, Lucio A1 - Tybjærg-Hansen, Anne A1 - Uitterlinden, Andre A1 - Ullgren, Abbe A1 - Ulstein, Ingun A1 - Valero, Sergi A1 - Valladares, Otto A1 - Broeckhoven, Christine Van A1 - Vance, Jeffery A1 - Vardarajan, Badri N A1 - van der Lugt, Aad A1 - Dongen, Jasper Van A1 - van Rooij, Jeroen A1 - van Swieten, John A1 - Vandenberghe, Rik A1 - Verhey, Frans A1 - Vidal, Jean-Sébastien A1 - Vogelgsang, Jonathan A1 - Vyhnalek, Martin A1 - Wagner, Michael A1 - Wallon, David A1 - Wang, Li-San A1 - Wang, Ruiqi A1 - Weinhold, Leonie A1 - Wiltfang, Jens A1 - Windle, Gill A1 - Woods, Bob A1 - Yannakoulia, Mary A1 - Zare, Habil A1 - Zhao, Yi A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Zulaica, Miren A1 - Farrer, Lindsay A A1 - Psaty, Bruce M A1 - Ghanbari, Mohsen A1 - Raj, Towfique A1 - Sachdev, Perminder A1 - Mather, Karen A1 - Jessen, Frank A1 - Ikram, M Arfan A1 - de Mendonça, Alexandre A1 - Hort, Jakub A1 - Tsolaki, Magda A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - Williams, Julie A1 - Frikke-Schmidt, Ruth A1 - Clarimon, Jordi A1 - Deleuze, Jean-Francois A1 - Rossi, Giacomina A1 - Seshadri, Sudha A1 - Andreassen, Ole A A1 - Ingelsson, Martin A1 - Hiltunen, Mikko A1 - Sleegers, Kristel A1 - Schellenberg, Gerard D A1 - van Duijn, Cornelia M A1 - Sims, Rebecca A1 - van der Flier, Wiesje M A1 - Ruiz, Agustin A1 - Ramirez, Alfredo A1 - Lambert, Jean-Charles KW - Alzheimer Disease KW - Cognitive Dysfunction KW - Genome-Wide Association Study KW - Humans KW - tau Proteins AB -

Characterization 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.

VL - 54 IS - 4 ER - TY - JOUR T1 - Non-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations. JF - Commun Biol Y1 - 2022 A1 - Elgart, Michael A1 - Lyons, Genevieve A1 - Romero-Brufau, Santiago A1 - Kurniansyah, Nuzulul A1 - Brody, Jennifer A A1 - Guo, Xiuqing A1 - Lin, Henry J A1 - Raffield, Laura A1 - Gao, Yan A1 - Chen, Han A1 - de Vries, Paul A1 - Lloyd-Jones, Donald M A1 - Lange, Leslie A A1 - Peloso, Gina M A1 - Fornage, Myriam A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Levy, Daniel A1 - Redline, Susan A1 - Sofer, Tamar KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Machine Learning KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide AB -

Polygenic 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.

VL - 5 IS - 1 ER - TY - JOUR T1 - {Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol JF - Diabetes Care Y1 - 2022 A1 - Wu, P. A1 - Moon, J. Y. A1 - Daghlas, I. A1 - Franco, G. A1 - Porneala, B. C. A1 - Ahmadizar, F. A1 - Richardson, T. G. A1 - Isaksen, J. L. A1 - Hindy, G. A1 - Yao, J. A1 - Sitlani, C. M. A1 - Raffield, L. M. A1 - Yanek, L. R. A1 - Feitosa, M. F. A1 - Cuadrat, R. R. C. A1 - Qi, Q. A1 - Arfan Ikram, M. A1 - Ellervik, C. A1 - Ericson, U. A1 - Goodarzi, M. O. A1 - Brody, J. A. A1 - Lange, L. A1 - Mercader, J. M. A1 - Vaidya, D. A1 - An, P. A1 - Schulze, M. B. A1 - Masana, L. A1 - Ghanbari, M. A1 - Olesen, M. S. A1 - Cai, J. A1 - Guo, X. A1 - Floyd, J. S. A1 - Jäger, S. A1 - Province, M. A. A1 - Kalyani, R. R. A1 - Psaty, B. M. A1 - Orho-Melander, M. A1 - Ridker, P. M. A1 - Kanters, J. K. A1 - Uitterlinden, A. A1 - Davey Smith, G. A1 - Gill, D. A1 - Kaplan, R. C. A1 - Kavousi, M. A1 - Raghavan, S. A1 - Chasman, D. I. A1 - Rotter, J. I. A1 - Meigs, J. B. A1 - Florez, J. C. A1 - Dupuis, J. A1 - Liu, C. T. A1 - Merino, J. AB - LDL 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. VL - 45 ER - TY - JOUR T1 - Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study. JF - EBioMedicine Y1 - 2022 A1 - Lemaitre, Rozenn N A1 - Jensen, Paul N A1 - Zeigler, Maxwell A1 - Fretts, Amanda M A1 - Umans, Jason G A1 - Howard, Barbara V A1 - Sitlani, Colleen M A1 - McKnight, Barbara A1 - Gharib, Sina A A1 - King, Irena B A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Totah, Rheem A KW - Animals KW - Arachidonic Acids KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - Eicosanoids KW - Humans KW - Ischemic Stroke KW - Prospective Studies AB -

BACKGROUND: 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.

VL - 83 ER - TY - JOUR T1 - Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts. JF - J Am Heart Assoc Y1 - 2022 A1 - Lamprea-Montealegre, Julio A A1 - Arnold, Alice M A1 - McClelland, Robyn L A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Biggs, Mary L A1 - Siscovick, David S A1 - Tracy, Russell P A1 - Beisswenger, Paul J A1 - Psaty, Bruce M A1 - Ix, Joachim H A1 - Kizer, Jorge R KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Glycation End Products, Advanced KW - Humans KW - Middle Aged KW - Risk Factors AB -

Background 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.

VL - 11 IS - 15 ER - TY - JOUR T1 - Plasma proteomic signature of decline in gait speed and grip strength. JF - Aging Cell Y1 - 2022 A1 - Liu, Xiaojuan A1 - Pan, Stephanie A1 - Xanthakis, Vanessa A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Austin, Thomas R A1 - Newman, Anne B A1 - Sanders, Jason L A1 - Wu, Chenkai A1 - Tracy, Russell P A1 - Gerszten, Robert E A1 - Odden, Michelle C KW - Adult KW - Female KW - Gait KW - Hand Strength KW - Humans KW - Independent Living KW - Male KW - Proteomics KW - Walking Speed AB -

The 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.

VL - 21 IS - 12 ER - TY - JOUR T1 - Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2022 A1 - Hu, Xiaowei A1 - Qiao, Dandi A1 - Kim, Wonji A1 - Moll, Matthew A1 - Balte, Pallavi P A1 - Lange, Leslie A A1 - Bartz, Traci M A1 - Kumar, Rajesh A1 - Li, Xingnan A1 - Yu, Bing A1 - Cade, Brian E A1 - Laurie, Cecelia A A1 - Sofer, Tamar A1 - Ruczinski, Ingo A1 - Nickerson, Deborah A A1 - Muzny, Donna M A1 - Metcalf, Ginger A A1 - Doddapaneni, Harshavardhan A1 - Gabriel, Stacy A1 - Gupta, Namrata A1 - Dugan-Perez, Shannon A1 - Cupples, L Adrienne A1 - Loehr, Laura R A1 - Jain, Deepti A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Morrison, Alanna C A1 - Vasan, Ramachandran S A1 - Washko, George A1 - Rich, Stephen S A1 - O'Connor, George T A1 - Bleecker, Eugene A1 - Kaplan, Robert C A1 - Kalhan, Ravi A1 - Redline, Susan A1 - Gharib, Sina A A1 - Meyers, Deborah A1 - Ortega, Victor A1 - Dupuis, Josée A1 - London, Stephanie J A1 - Lappalainen, Tuuli A1 - Oelsner, Elizabeth C A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Thornton, Timothy A A1 - Wheeler, Heather E A1 - Cho, Michael H A1 - Im, Hae Kyung A1 - Manichaikul, Ani AB -

While 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.

ER - TY - JOUR T1 - {A population-based meta-analysis of circulating GFAP for cognition and dementia risk JF - Ann Clin Transl Neurol Y1 - 2022 A1 - Gonzales, M. M. A1 - Wiedner, C. A1 - Wang, C. P. A1 - Liu, Q. A1 - Bis, J. C. A1 - Li, Z. A1 - Himali, J. J. A1 - Ghosh, S. A1 - Thomas, E. A. A1 - Parent, D. M. A1 - Kautz, T. F. A1 - Pase, M. P. A1 - Aparicio, H. J. A1 - Djousse, L. A1 - Mukamal, K. J. A1 - Psaty, B. M. A1 - Longstreth, W. T. A1 - Mosley, T. H. A1 - Gudnason, V. A1 - Mbangdadji, D. A1 - Lopez, O. L. A1 - Yaffe, K. A1 - Sidney, S. A1 - Bryan, R. N. A1 - Nasrallah, I. M. A1 - DeCarli, C. S. A1 - Beiser, A. S. A1 - Launer, L. J. A1 - Fornage, M. A1 - Tracy, R. P. A1 - Seshadri, S. A1 - Satizabal, C. L. AB - Expression 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. VL - 9 ER - TY - JOUR T1 - Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing. JF - Eur J Epidemiol Y1 - 2022 A1 - Austin, Thomas R A1 - McHugh, Caitlin P A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Sitlani, Colleen M A1 - Bartz, Traci M A1 - Biggs, Mary L A1 - Bansal, Nisha A1 - Bůzková, Petra A1 - Carr, Steven A A1 - deFilippi, Christopher R A1 - Elkind, Mitchell S V A1 - Fink, Howard A A1 - Floyd, James S A1 - Fohner, Alison E A1 - Gerszten, Robert E A1 - Heckbert, Susan R A1 - Katz, Daniel H A1 - Kizer, Jorge R A1 - Lemaitre, Rozenn N A1 - Longstreth, W T A1 - McKnight, Barbara A1 - Mei, Hao A1 - Mukamal, Kenneth J A1 - Newman, Anne B A1 - Ngo, Debby A1 - Odden, Michelle C A1 - Vasan, Ramachandran S A1 - Shojaie, Ali A1 - Simon, Noah A1 - Smith, George Davey A1 - Davies, Neil M A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Tracy, Russell P A1 - Wiggins, Kerri L A1 - Zheng, Jie A1 - Psaty, Bruce M AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. JF - Am J Hum Genet Y1 - 2022 A1 - Hindy, George A1 - Dornbos, Peter A1 - Chaffin, Mark D A1 - Liu, Dajiang J A1 - Wang, Minxian A1 - Selvaraj, Margaret Sunitha A1 - Zhang, David A1 - Park, Joseph A1 - Aguilar-Salinas, Carlos A A1 - Antonacci-Fulton, Lucinda A1 - Ardissino, Diego A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Atzmon, Gil A1 - Ballantyne, Christie M A1 - Barajas-Olmos, Francisco A1 - Barzilai, Nir A1 - Becker, Lewis C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bottinger, Erwin A1 - Bowden, Donald W A1 - Bown, Matthew J A1 - Brody, Jennifer A A1 - Broome, Jai G A1 - Burtt, Noel P A1 - Cade, Brian E A1 - Centeno-Cruz, Federico A1 - Chan, Edmund A1 - Chang, Yi-Cheng A1 - Chen, Yii-der I A1 - Cheng, Ching-Yu A1 - Choi, Won Jung A1 - Chowdhury, Rajiv A1 - Contreras-Cubas, Cecilia A1 - Córdova, Emilio J A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Danesh, John A1 - de Vries, Paul S A1 - DeFronzo, Ralph A A1 - Doddapaneni, Harsha A1 - Duggirala, Ravindranath A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Emery, Leslie S A1 - Florez, Jose C A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Fuster, Valentin A1 - Garay-Sevilla, Ma Eugenia A1 - García-Ortiz, Humberto A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Gieger, Christian A1 - Glaser, Benjamin A1 - Gonzalez, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Graff, Mariaelisa A1 - Graham, Sarah E A1 - Grarup, Niels A1 - Groop, Leif C A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Han, Sohee A1 - Hanis, Craig L A1 - Hansen, Torben A1 - He, Jiang A1 - Heard-Costa, Nancy L A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Irvin, Marguerite R A1 - Islas-Andrade, Sergio A1 - Jarvik, Gail P A1 - Kang, Hyun Min A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Kenny, Eimear E A1 - Khan, Alyna T A1 - Kim, Bong-Jo A1 - Kim, Ryan W A1 - Kim, Young Jin A1 - Koistinen, Heikki A A1 - Kooperberg, Charles A1 - Kuusisto, Johanna A1 - Kwak, Soo Heon A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lee, Jiwon A1 - Lee, Juyoung A1 - Lee, Seonwook A1 - Lehman, Donna M A1 - Lemaitre, Rozenn N A1 - Linneberg, Allan A1 - Liu, Jianjun A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Lyssenko, Valeriya A1 - Ma, Ronald C W A1 - Martin, Lisa Warsinger A1 - Martínez-Hernández, Angélica A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - McPherson, Ruth A1 - Meigs, James B A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mendoza-Caamal, Elvia A1 - Metcalf, Ginger A A1 - Mi, Xuenan A1 - Mohlke, Karen L A1 - Montasser, May E A1 - Moon, Jee-Young A1 - Moreno-Macias, Hortensia A1 - Morrison, Alanna C A1 - Muzny, Donna M A1 - Nelson, Sarah C A1 - Nilsson, Peter M A1 - O'Connell, Jeffrey R A1 - Orho-Melander, Marju A1 - Orozco, Lorena A1 - Palmer, Colin N A A1 - Palmer, Nicholette D A1 - Park, Cheol Joo A1 - Park, Kyong Soo A1 - Pedersen, Oluf A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Post, Wendy S A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qi, Qibin A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Revilla-Monsalve, Cristina A1 - Rich, Stephen S A1 - Samani, Nilesh A1 - Schunkert, Heribert A1 - Schurmann, Claudia A1 - Seo, Daekwan A1 - Seo, Jeong-Sun A1 - Sim, Xueling A1 - Sladek, Rob A1 - Small, Kerrin S A1 - So, Wing Yee A1 - Stilp, Adrienne M A1 - Tai, E Shyong A1 - Tam, Claudia H T A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Thameem, Farook A1 - Tomlinson, Brian A1 - Tsai, Michael Y A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - van Dam, Rob M A1 - Vasan, Ramachandran S A1 - Viaud Martinez, Karine A A1 - Wang, Fei Fei A1 - Wang, Xuzhi A1 - Watkins, Hugh A1 - Weeks, Daniel E A1 - Wilson, James G A1 - Witte, Daniel R A1 - Wong, Tien-Yin A1 - Yanek, Lisa R A1 - Kathiresan, Sekar A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Natarajan, Pradeep A1 - Flannick, Jason A A1 - Khera, Amit V A1 - Peloso, Gina M KW - Alleles KW - Blood Glucose KW - Case-Control Studies KW - Computational Biology KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Molecular Sequence Annotation KW - Multifactorial Inheritance KW - Open Reading Frames KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Large-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.

VL - 109 IS - 1 ER - TY - JOUR T1 - Rare genetic variants explain missing heritability in smoking. JF - Nat Hum Behav Y1 - 2022 A1 - Jang, Seon-Kyeong A1 - Evans, Luke A1 - Fialkowski, Allison A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Blangero, John A1 - Bleecker, Eugene R A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Jenkins, Brenda W Campbell A1 - Carson, April P A1 - Chavan, Sameer A1 - Cupples, L Adrienne A1 - Custer, Brian A1 - Damrauer, Scott M A1 - David, Sean P A1 - de Andrade, Mariza A1 - Dinardo, Carla L A1 - Fingerlin, Tasha E A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Glahn, David C A1 - Haessler, Jeffrey A1 - Heckbert, Susan R A1 - Hokanson, John E A1 - Hou, Lifang A1 - Hwang, Shih-Jen A1 - Hyman, Matthew C A1 - Judy, Renae A1 - Justice, Anne E A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Kim, Wonji A1 - Kooperberg, Charles A1 - Levy, Daniel A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Manichaikul, Ani W A1 - Gladwin, Mark T A1 - Martin, Lisa Warsinger A1 - Nouraie, Mehdi A1 - Melander, Olle A1 - Meyers, Deborah A A1 - Montgomery, Courtney G A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Palmer, Nicholette D A1 - Payton, Marinelle A1 - Peljto, Anna L A1 - Peyser, Patricia A A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qiao, Dandi A1 - Rader, Daniel J A1 - Rafaels, Nicholas A1 - Redline, Susan A1 - Reed, Robert M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Silverman, Edwin K A1 - Smith, Nicholas L A1 - Smith, J Gustav A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Vasan, Ramachandran S A1 - Gordeuk, Victor R A1 - Wang, Zhe A1 - Wiggins, Kerri L A1 - Yanek, Lisa R A1 - Yang, Ivana V A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhang, Yingze A1 - Liu, Dajiang J A1 - Keller, Matthew C A1 - Vrieze, Scott AB -

Common 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.

ER - TY - JOUR T1 - Relation of Cigarette Smoking and Heart Failure in Adults ≥65 Years of Age (From the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2022 A1 - Gottdiener, John S A1 - Bůzková, Petra A1 - Kahn, Peter A A1 - DeFilippi, Christopher A1 - Shah, Sanjiv A1 - Barasch, Eddy A1 - Kizer, Jorge R A1 - Psaty, Bruce A1 - Gardin, Julius M AB -

Cigarette 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.

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A1 - Liu, J. A1 - Loeffler, M. A1 - London, B. A1 - Lubitz, S. A. A1 - Lye, S. J. A1 - Mackey, D. A. A1 - gi, R. A1 - Magnusson, P. K. E. A1 - Marcus, G. M. A1 - Vidal, P. M. A1 - Martin, N. G. A1 - rz, W. A1 - Matsuda, F. A1 - McGarrah, R. W. A1 - McGue, M. A1 - McKnight, A. J. A1 - Medland, S. E. A1 - m, D. A1 - Metspalu, A. A1 - Mitchell, B. D. A1 - Mitchell, P. A1 - Mook-Kanamori, D. O. A1 - Morris, A. D. A1 - Mucci, L. A. A1 - Munroe, P. B. A1 - Nalls, M. A. A1 - Nazarian, S. A1 - Nelson, A. E. A1 - Neville, M. J. A1 - Newton-Cheh, C. A1 - Nielsen, C. S. A1 - then, M. M. A1 - Ohlsson, C. A1 - Oldehinkel, A. J. A1 - Orozco, L. A1 - Pahkala, K. A1 - Pajukanta, P. A1 - Palmer, C. N. A. A1 - Parra, E. J. A1 - Pattaro, C. A1 - Pedersen, O. A1 - Pennell, C. E. A1 - Penninx, B. W. J. H. A1 - Pérusse, L. A1 - Peters, A. A1 - Peyser, P. A. A1 - Porteous, D. J. A1 - Posthuma, D. A1 - Power, C. A1 - Pramstaller, P. P. A1 - Province, M. A. A1 - Qi, Q. A1 - Qu, J. A1 - Rader, D. J. A1 - Raitakari, O. T. A1 - Ralhan, S. A1 - Rallidis, L. S. A1 - Rao, D. C. A1 - Redline, S. A1 - Reilly, D. F. A1 - Reiner, A. P. A1 - Rhee, S. Y. A1 - Ridker, P. M. A1 - Rienstra, M. A1 - Ripatti, S. A1 - Ritchie, M. D. A1 - Roden, D. M. A1 - Rosendaal, F. R. A1 - Rotter, J. I. A1 - Rudan, I. A1 - Rutters, F. A1 - Sabanayagam, C. A1 - Saleheen, D. A1 - Salomaa, V. A1 - Samani, N. J. A1 - Sanghera, D. K. A1 - Sattar, N. A1 - Schmidt, B. A1 - Schmidt, H. A1 - Schmidt, R. A1 - Schulze, M. B. A1 - Schunkert, H. A1 - Scott, L. J. A1 - Scott, R. J. A1 - Sever, P. A1 - Shiroma, E. J. A1 - Shoemaker, M. B. A1 - Shu, X. O. A1 - Simonsick, E. M. A1 - Sims, M. A1 - Singh, J. R. A1 - Singleton, A. B. A1 - Sinner, M. F. A1 - Smith, J. G. A1 - Snieder, H. A1 - Spector, T. D. A1 - Stampfer, M. J. A1 - Stark, K. J. A1 - Strachan, D. P. A1 - 't Hart, L. M. A1 - Tabara, Y. A1 - Tang, H. A1 - Tardif, J. C. A1 - Thanaraj, T. A. A1 - Timpson, N. J. A1 - njes, A. A1 - Tremblay, A. A1 - Tuomi, T. A1 - Tuomilehto, J. A1 - -Luna, M. T. A1 - Uitterlinden, A. G. A1 - van Dam, R. M. A1 - van der Harst, P. A1 - Van der Velde, N. A1 - van Duijn, C. M. A1 - van Schoor, N. M. A1 - Vitart, V. A1 - lker, U. A1 - Vollenweider, P. A1 - lzke, H. A1 - Wacher-Rodarte, N. H. A1 - Walker, M. A1 - Wang, Y. X. A1 - Wareham, N. J. A1 - Watanabe, R. M. A1 - Watkins, H. A1 - Weir, D. R. A1 - Werge, T. M. A1 - Widén, E. A1 - Wilkens, L. R. A1 - Willemsen, G. A1 - Willett, W. C. A1 - Wilson, J. F. A1 - Wong, T. Y. A1 - Woo, J. T. A1 - Wright, A. F. A1 - Wu, J. Y. A1 - Xu, H. A1 - Yajnik, C. S. A1 - Yokota, M. A1 - Yuan, J. M. A1 - Zeggini, E. A1 - Zemel, B. S. A1 - Zheng, W. A1 - Zhu, X. A1 - Zmuda, J. M. A1 - Zonderman, A. B. A1 - Zwart, J. A. A1 - Chasman, D. I. A1 - Cho, Y. S. A1 - Heid, I. M. A1 - McCarthy, M. I. A1 - Ng, M. C. Y. A1 - O'Donnell, C. J. A1 - Rivadeneira, F. A1 - Thorsteinsdottir, U. A1 - Sun, Y. V. A1 - Tai, E. S. A1 - Boehnke, M. A1 - Deloukas, P. A1 - Justice, A. E. A1 - Lindgren, C. M. A1 - Loos, R. J. F. A1 - Mohlke, K. L. A1 - North, K. E. A1 - Stefansson, K. A1 - Walters, R. G. A1 - Winkler, T. W. A1 - Young, K. L. A1 - Loh, P. R. A1 - Yang, J. A1 - Esko, T. A1 - Assimes, T. L. A1 - Auton, A. A1 - Abecasis, G. R. A1 - Willer, C. J. A1 - Locke, A. E. A1 - Berndt, S. I. A1 - Lettre, G. A1 - Frayling, T. M. A1 - Okada, Y. A1 - Wood, A. R. A1 - Visscher, P. M. A1 - Hirschhorn, J. N. A1 - Partida, G. C. A1 - Sun, Y. A1 - Croteau-Chonka, D. A1 - Vonk, J. M. A1 - Chanock, S. A1 - Le Marchand, L. AB - ) 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. VL - 610 ER - TY - JOUR T1 - Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults. JF - J Am Geriatr Soc Y1 - 2022 A1 - Gao, Hans A1 - Patel, Sheena A1 - Fohtung, Raymond B A1 - Cawthon, Peggy M A1 - Newman, Anne B A1 - Cauley, Jane A A1 - Carbone, Laura A1 - Chaves, Paulo H M A1 - Stein, Phyllis K A1 - Civitelli, Roberto A1 - Kizer, Jorge R AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Sleep problems and risk of cancer incidence and mortality in an older cohort: The Cardiovascular Health Study (CHS). JF - Cancer Epidemiol Y1 - 2022 A1 - Sillah, Arthur A1 - Watson, Nathaniel F A1 - Peters, Ulrike A1 - Biggs, Mary L A1 - Nieto, F Javier A1 - Li, Christopher I A1 - Gozal, David A1 - Thornton, Timothy A1 - Barrie, Sonnah A1 - Phipps, Amanda I AB -

BACKGROUND: 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.

VL - 76 ER - TY - JOUR T1 - Stroke genetics informs drug discovery and risk prediction across ancestries. JF - Nature Y1 - 2022 A1 - Mishra, Aniket A1 - Malik, Rainer A1 - Hachiya, Tsuyoshi A1 - Jürgenson, Tuuli A1 - Namba, Shinichi A1 - Posner, Daniel C A1 - Kamanu, Frederick K A1 - Koido, Masaru A1 - Le Grand, Quentin A1 - Shi, Mingyang A1 - He, Yunye A1 - Georgakis, Marios K A1 - Caro, Ilana A1 - Krebs, Kristi A1 - Liaw, Yi-Ching A1 - Vaura, Felix C A1 - Lin, Kuang A1 - Winsvold, Bendik Slagsvold A1 - Srinivasasainagendra, Vinodh A1 - Parodi, Livia A1 - Bae, Hee-Joon A1 - Chauhan, Ganesh A1 - Chong, Michael R A1 - Tomppo, Liisa A1 - Akinyemi, Rufus A1 - Roshchupkin, Gennady V A1 - Habib, Naomi A1 - Jee, Yon Ho A1 - Thomassen, Jesper Qvist A1 - Abedi, Vida A1 - Cárcel-Márquez, Jara A1 - Nygaard, Marianne A1 - Leonard, Hampton L A1 - Yang, Chaojie A1 - Yonova-Doing, Ekaterina A1 - Knol, Maria J A1 - Lewis, Adam J A1 - Judy, Renae L A1 - Ago, Tetsuro A1 - Amouyel, Philippe A1 - Armstrong, Nicole D A1 - Bakker, Mark K A1 - Bartz, Traci M A1 - Bennett, David A A1 - Bis, Joshua C A1 - Bordes, Constance A1 - Børte, Sigrid A1 - Cain, Anael A1 - Ridker, Paul M A1 - Cho, Kelly A1 - Chen, Zhengming A1 - Cruchaga, Carlos A1 - Cole, John W A1 - De Jager, Phil L A1 - de Cid, Rafael A1 - Endres, Matthias A1 - Ferreira, Leslie E A1 - Geerlings, Mirjam I A1 - Gasca, Natalie C A1 - Gudnason, Vilmundur A1 - Hata, Jun A1 - He, Jing A1 - Heath, Alicia K A1 - Ho, Yuk-Lam A1 - Havulinna, Aki S A1 - Hopewell, Jemma C A1 - Hyacinth, Hyacinth I A1 - Inouye, Michael A1 - Jacob, Mina A A1 - Jeon, Christina E A1 - Jern, Christina A1 - Kamouchi, Masahiro A1 - Keene, Keith L A1 - Kitazono, Takanari A1 - Kittner, Steven J A1 - Konuma, Takahiro A1 - Kumar, Amit A1 - Lacaze, Paul A1 - Launer, Lenore J A1 - Lee, Keon-Joo A1 - Lepik, Kaido A1 - Li, Jiang A1 - Li, Liming A1 - Manichaikul, Ani A1 - Markus, Hugh S A1 - Marston, Nicholas A A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Montellano, Felipe A A1 - Morisaki, Takayuki A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Nordestgaard, Børge G A1 - O'Donnell, Martin J A1 - Okada, Yukinori A1 - Onland-Moret, N Charlotte A1 - Ovbiagele, Bruce A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rosand, Jonathan A1 - Sabatine, Marc S A1 - Sacco, Ralph L A1 - Saleheen, Danish A1 - Sandset, Else Charlotte A1 - Salomaa, Veikko A1 - Sargurupremraj, Muralidharan A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Schmidt, Carsten O A1 - Shimizu, Atsushi A1 - Smith, Nicholas L A1 - Sloane, Kelly L A1 - Sutoh, Yoichi A1 - Sun, Yan V A1 - Tanno, Kozo A1 - Tiedt, Steffen A1 - Tatlisumak, Turgut A1 - Torres-Aguila, Nuria P A1 - Tiwari, Hemant K A1 - Trégouët, David-Alexandre A1 - Trompet, Stella A1 - Tuladhar, Anil Man A1 - Tybjærg-Hansen, Anne A1 - van Vugt, Marion A1 - Vibo, Riina A1 - Verma, Shefali S A1 - Wiggins, Kerri L A1 - Wennberg, Patrik A1 - Woo, Daniel A1 - Wilson, Peter W F A1 - Xu, Huichun A1 - Yang, Qiong A1 - Yoon, Kyungheon A1 - Millwood, Iona Y A1 - Gieger, Christian A1 - Ninomiya, Toshiharu A1 - Grabe, Hans J A1 - Jukema, J Wouter A1 - Rissanen, Ina L A1 - Strbian, Daniel A1 - Kim, Young Jin A1 - Chen, Pei-Hsin A1 - Mayerhofer, Ernst A1 - Howson, Joanna M M A1 - Irvin, Marguerite R A1 - Adams, Hieab A1 - Wassertheil-Smoller, Sylvia A1 - Christensen, Kaare A1 - Ikram, Mohammad A A1 - Rundek, Tatjana A1 - Worrall, Bradford B A1 - Lathrop, G Mark A1 - Riaz, Moeen A1 - Simonsick, Eleanor M A1 - Kõrv, Janika A1 - França, Paulo H C A1 - Zand, Ramin A1 - Prasad, Kameshwar A1 - Frikke-Schmidt, Ruth A1 - de Leeuw, Frank-Erik A1 - Liman, Thomas A1 - Haeusler, Karl Georg A1 - Ruigrok, Ynte M A1 - Heuschmann, Peter Ulrich A1 - Longstreth, W T A1 - Jung, Keum Ji A1 - Bastarache, Lisa A1 - Paré, Guillaume A1 - Damrauer, Scott M A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Anderson, Christopher D A1 - Zwart, John-Anker A1 - Niiranen, Teemu J A1 - Fornage, Myriam A1 - Liaw, Yung-Po A1 - Seshadri, Sudha A1 - Fernandez-Cadenas, Israel A1 - Walters, Robin G A1 - Ruff, Christian T A1 - Owolabi, Mayowa O A1 - Huffman, Jennifer E A1 - Milani, Lili A1 - Kamatani, Yoichiro A1 - Dichgans, Martin A1 - Debette, Stephanie AB -

Previous 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.

ER - TY - JOUR T1 - Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. JF - Am J Respir Crit Care Med Y1 - 2022 A1 - Liang, Jingjing A1 - Wang, Heming A1 - Cade, Brian E A1 - Kurniansyah, Nuzulul A1 - He, Karen Y A1 - Lee, Jiwon A1 - Sands, Scott A A1 - Brody, Jennifer A1 - Chen, Han A1 - Gottlieb, Daniel J A1 - Evans, Daniel S A1 - Guo, Xiuqing A1 - Gharib, Sina A A1 - Hale, Lauren A1 - Hillman, David R A1 - Lutsey, Pamela L A1 - Mukherjee, Sutapa A1 - Ochs-Balcom, Heather M A1 - Palmer, Lyle J A1 - Purcell, Shaun A1 - Saxena, Richa A1 - Patel, Sanjay R A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Boerwinkle, Eric A1 - Lin, Xihong A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Manichaikul, Ani A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Redline, Susan A1 - Zhu, Xiaofeng AB -

INTRODUCTION: 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.

ER - TY - JOUR T1 - The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. JF - Front Endocrinol (Lausanne) Y1 - 2022 A1 - Wang, Zhe A1 - Choi, Shing Wan A1 - Chami, Nathalie A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Redline, Susan A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Kim, Wonji A1 - McDonald, Merry-Lynn N A1 - Regan, Elizabeth A A1 - Silverman, Edwin K A1 - Liu, Ching-Ti A1 - Vasan, Ramachandran S A1 - Kalyani, Rita R A1 - Mathias, Rasika A A1 - Yanek, Lisa R A1 - Arnett, Donna K A1 - Justice, Anne E A1 - North, Kari E A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Lange, Leslie A A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Ellinor, Patrick T A1 - Lubitz, Steven A A1 - Blangero, John A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Gladwin, Mark T A1 - Albert, Christine M A1 - Chasman, Daniel I A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - O'Reilly, Paul F A1 - Loos, Ruth J F KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Whole Genome Sequencing AB -

Polygenic 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.

VL - 13 ER - TY - JOUR T1 - Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. JF - Hum Mol Genet Y1 - 2022 A1 - Pankratz, Nathan A1 - Wei, Peng A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Vries, Paul S A1 - Huffman, Jennifer E A1 - Stimson, Mary Rachel A1 - Auer, Paul L A1 - Boerwinkle, Eric A1 - Cushman, Mary A1 - Maat, Moniek P M A1 - Folsom, Aaron R A1 - Franco, Oscar H A1 - Gibbs, Richard A A1 - Haagenson, Kelly K A1 - Hofman, Albert A1 - Johnsen, Jill M A1 - Kovar, Christie L A1 - Kraaij, Robert A1 - McKnight, Barbara A1 - Metcalf, Ginger A A1 - Muzny, Donna A1 - Psaty, Bruce M A1 - Tang, Weihong A1 - Uitterlinden, André G A1 - Rooij, Jeroen G J A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Reiner, Alex P A1 - Morrison, Alanna C A1 - Smith, Nicholas L AB -

Plasma 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.

ER - TY - JOUR T1 - Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. JF - Commun Biol Y1 - 2022 A1 - DiCorpo, Daniel A1 - Gaynor, Sheila M A1 - Russell, Emily M A1 - Westerman, Kenneth E A1 - Raffield, Laura M A1 - Majarian, Timothy D A1 - Wu, Peitao A1 - Sarnowski, Chloe A1 - Highland, Heather M A1 - Jackson, Anne A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Brody, Jennifer A A1 - Hidalgo, Bertha A1 - Guo, Xiuqing A1 - Perry, James A A1 - O'Connell, Jeffrey R A1 - Lent, Samantha A1 - Montasser, May E A1 - Cade, Brian E A1 - Jain, Deepti A1 - Wang, Heming A1 - D'Oliveira Albanus, Ricardo A1 - Varshney, Arushi A1 - Yanek, Lisa R A1 - Lange, Leslie A1 - Palmer, Nicholette D A1 - Almeida, Marcio A1 - Peralta, Juan M A1 - Aslibekyan, Stella A1 - Baldridge, Abigail S A1 - Bertoni, Alain G A1 - Bielak, Lawrence F A1 - Chen, Chung-Shiuan A1 - Chen, Yii-Der Ida A1 - Choi, Won Jung A1 - Goodarzi, Mark O A1 - Floyd, James S A1 - Irvin, Marguerite R A1 - Kalyani, Rita R A1 - Kelly, Tanika N A1 - Lee, Seonwook A1 - Liu, Ching-Ti A1 - Loesch, Douglas A1 - Manson, JoAnn E A1 - Minster, Ryan L A1 - Naseri, Take A1 - Pankow, James S A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Selvin, Elizabeth A1 - Smith, Jennifer A A1 - Weeks, Daniel E A1 - Xu, Huichun A1 - Yao, Jie A1 - Zhao, Wei A1 - Parker, Stephen A1 - Alonso, Alvaro A1 - Arnett, Donna K A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Duggirala, Ravindranath A1 - He, Jiang A1 - Heckbert, Susan R A1 - Kardia, Sharon L R A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Liu, Simin A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Florez, Jose C A1 - Wilson, James G A1 - Sladek, Robert A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Dupuis, Josée A1 - Meigs, James B A1 - Wessel, Jennifer A1 - Manning, Alisa K KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Glucose KW - Humans KW - Insulin KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Precision Medicine KW - Receptors, Immunologic KW - United States AB -

The 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.

VL - 5 IS - 1 ER - TY - JOUR T1 - Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. JF - Nat Commun Y1 - 2022 A1 - Wheeler, Marsha M A1 - Stilp, Adrienne M A1 - Rao, Shuquan A1 - Halldorsson, Bjarni V A1 - Beyter, Doruk A1 - Wen, Jia A1 - Mihkaylova, Anna V A1 - McHugh, Caitlin P A1 - Lane, John A1 - Jiang, Min-Zhi A1 - Raffield, Laura M A1 - Jun, Goo A1 - Sedlazeck, Fritz J A1 - Metcalf, Ginger A1 - Yao, Yao A1 - Bis, Joshua B A1 - Chami, Nathalie A1 - de Vries, Paul S A1 - Desai, Pinkal A1 - Floyd, James S A1 - Gao, Yan A1 - Kammers, Kai A1 - Kim, Wonji A1 - Moon, Jee-Young A1 - Ratan, Aakrosh A1 - Yanek, Lisa R A1 - Almasy, Laura A1 - Becker, Lewis C A1 - Blangero, John A1 - Cho, Michael H A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Lewis, Joshua P A1 - Loos, Ruth J F A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tang, Hua A1 - Tracy, Russell P A1 - Boerwinkle, Eric A1 - Abecasis, Goncalo R A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Nickerson, Deborah A A1 - Conomos, Matthew P A1 - Li, Yun A1 - Þorsteinsdottir, Unnur A1 - Magnússon, Magnús K A1 - Stefansson, Kari A1 - Pankratz, Nathan D A1 - Bauer, Daniel E A1 - Auer, Paul L A1 - Reiner, Alex P KW - Blood Cells KW - Genome-Wide Association Study KW - Humans KW - Whole Genome Sequencing AB -

Genome-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.

VL - 13 IS - 1 ER - TY - JOUR T1 - Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. JF - Hum Mol Genet Y1 - 2022 A1 - Pan, Yang A1 - Sun, Xiao A1 - Mi, Xuenan A1 - Huang, Zhijie A1 - Hsu, Yenchih A1 - Hixson, James E A1 - Munzy, Donna A1 - Metcalf, Ginger A1 - Franceschini, Nora A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Francis, Michael A1 - Brody, Jennifer A A1 - Kestenbaum, Bryan A1 - Sitlani, Colleen M A1 - Mychaleckyj, Josyf C A1 - Kramer, Holly A1 - Lange, Leslie A A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Irvin, Marguerite R A1 - Smith, Jennifer A A1 - Yanek, Lisa R A1 - Vaidya, Dhananjay A1 - Chen, Yii-Der Ida A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Cupple, L Adrienne A1 - Levy, Daniel A1 - Kaplan, Robert C A1 - North, Kari E A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Gibbs, Richard A A1 - Morrison, Alanna C A1 - Feldman, Harold A1 - Boerwinkle, Eric A1 - He, Jiang A1 - Kelly, Tanika N AB -

Diabetic 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.

ER - TY - JOUR T1 - {Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project JF - Stroke Y1 - 2022 A1 - Hu, Y. A1 - Haessler, J. W. A1 - Manansala, R. A1 - Wiggins, K. L. A1 - Moscati, A. A1 - Beiser, A. A1 - Heard-Costa, N. L. A1 - Sarnowski, C. A1 - Raffield, L. M. A1 - Chung, J. A1 - Marini, S. A1 - Anderson, C. D. A1 - Rosand, J. A1 - Xu, H. A1 - Sun, X. A1 - Kelly, T. N. A1 - Wong, Q. A1 - Lange, L. A. A1 - Rotter, J. I. A1 - Correa, A. A1 - Vasan, R. S. A1 - Seshadri, S. A1 - Rich, S. S. A1 - Do, R. A1 - Loos, R. J. F. A1 - Longstreth, W. T. A1 - Bis, J. C. A1 - Psaty, B. M. A1 - Tirschwell, D. L. A1 - Assimes, T. L. A1 - Silver, B. A1 - Liu, S. A1 - Jackson, R. A1 - Wassertheil-Smoller, S. A1 - Mitchell, B. D. A1 - Fornage, M. A1 - Auer, P. L. A1 - Reiner, A. P. A1 - Kooperberg, C. AB - Stroke 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. VL - 53 ER - TY - JOUR T1 - Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. JF - Nature Y1 - 2023 A1 - Weinstock, Joshua S A1 - Gopakumar, Jayakrishnan A1 - Burugula, Bala Bharathi A1 - Uddin, Md Mesbah A1 - Jahn, Nikolaus A1 - Belk, Julia A A1 - Bouzid, Hind A1 - Daniel, Bence A1 - Miao, Zhuang A1 - Ly, Nghi A1 - Mack, Taralynn M A1 - Luna, Sofia E A1 - Prothro, Katherine P A1 - Mitchell, Shaneice R A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Sinner, Moritz F A1 - von Falkenhausen, Aenne S A1 - Kääb, Stefan A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Redline, Susan A1 - Cade, Brian E A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - DeMeo, Dawn L A1 - Vasan, Ramachandran S A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - He, Jiang A1 - Rienstra, Michiel A1 - van der Harst, Pim A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Cutler, Michael J A1 - Knight, Stacey A1 - Muhlestein, J Brent A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Smith, J Gustav A1 - Melander, Olle A1 - Nilsson, Peter M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - McGarvey, Stephen A1 - Williams, L Keoki A1 - Xiao, Shujie A1 - Yang, Mao A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Marcus, Gregory M A1 - Kane, John P A1 - Pullinger, Clive R A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan M A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Zhou, Ying A1 - Manson, JoAnn E A1 - Desai, Pinkal A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Satpathy, Ansuman T A1 - Natarajan, Pradeep A1 - Kitzman, Jacob O A1 - Whitsel, Eric A A1 - Reiner, Alexander P A1 - Bick, Alexander G A1 - Jaiswal, Siddhartha KW - Alleles KW - Animals KW - Clonal Hematopoiesis KW - Genome-Wide Association Study KW - Hematopoiesis KW - Hematopoietic Stem Cells KW - Humans KW - Mice KW - Mutation KW - Promoter Regions, Genetic AB -

Mutations 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.

VL - 616 IS - 7958 ER - TY - JOUR T1 - Association Between Acute Myocardial Infarction and Cognition. JF - JAMA Neurol Y1 - 2023 A1 - Johansen, Michelle C A1 - Ye, Wen A1 - Gross, Alden A1 - Gottesman, Rebecca F A1 - Han, Dehua A1 - Whitney, Rachael A1 - Briceño, Emily M A1 - Giordani, Bruno J A1 - Shore, Supriya A1 - Elkind, Mitchell S V A1 - Manly, Jennifer J A1 - Sacco, Ralph L A1 - Fohner, Alison A1 - Griswold, Michael A1 - Psaty, Bruce M A1 - Sidney, Stephen A1 - Sussman, Jeremy A1 - Yaffe, Kristine A1 - Moran, Andrew E A1 - Heckbert, Susan A1 - Hughes, Timothy M A1 - Galecki, Andrzej A1 - Levine, Deborah A AB -

IMPORTANCE: 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.

ER - TY - JOUR T1 - Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. JF - J Am Heart Assoc Y1 - 2023 A1 - Liu, Xue A1 - Sun, Xianbang A1 - Zhang, Yuankai A1 - Jiang, Wenqing A1 - Lai, Meng A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Haessler, Jeffrey A1 - Zheng, Yinan A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Qian, Yong A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Carson, April P A1 - Abecasis, Goncalo A1 - Dupuis, Josée A1 - Reiner, Alexander A1 - Kooperberg, Charles A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Background 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.

ER - TY - JOUR T1 - Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study. JF - Calcif Tissue Int Y1 - 2023 A1 - Elam, Rachel E A1 - Bůzková, Petra A1 - Delaney, Joseph A C A1 - Fink, Howard A A1 - Barzilay, Joshua I A1 - Carbone, Laura D A1 - Saha, Rick A1 - Robbins, John A A1 - Mukamal, Kenneth J A1 - Valderrábano, Rodrigo J A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Olson, Nels C A1 - Huber, Sally A A1 - Doyle, Margaret F A1 - Landay, Alan L A1 - Cauley, Jane A AB -

In 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.

ER - TY - JOUR T1 - Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. JF - Neurology Y1 - 2023 A1 - Zhang, Yuankai A1 - Liu, Xue A1 - Wiggins, Kerri L A1 - Kurniansyah, Nuzulul A1 - Guo, Xiuqing A1 - Rodrigue, Amanda L A1 - Zhao, Wei A1 - Yanek, Lisa R A1 - Ratliff, Scott M A1 - Pitsillides, Achilleas A1 - Aguirre Patiño, Juan Sebastian A1 - Sofer, Tamar A1 - Arking, Dan E A1 - Austin, Thomas R A1 - Beiser, Alexa S A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Curran, Joanne E A1 - Hou, Lifang A1 - Hughes, Timothy M A1 - Kardia, Sharon L A1 - Launer, Lenore A1 - Levy, Daniel A1 - Mosley, Tom H A1 - Nasrallah, Ilya M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Tarraf, Wassim A1 - González, Kevin A A1 - Ramachandran, Vasan A1 - Yaffe, Kristine A1 - Nyquist, Paul A A1 - Psaty, Bruce M A1 - DeCarli, Charles S A1 - Smith, Jennifer A A1 - Glahn, David C A1 - González, Hector M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Heckbert, Susan R A1 - Fitzpatrick, Annette L A1 - Liu, Chunyu A1 - Satizabal, Claudia L AB -

BACKGROUND 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.

ER - TY - JOUR T1 - Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. JF - BMJ Y1 - 2023 A1 - Ong, Kwok Leung A1 - Marklund, Matti A1 - Huang, Liping A1 - Rye, Kerry-Anne A1 - Hui, Nicholas A1 - Pan, Xiong-Fei A1 - Rebholz, Casey M A1 - Kim, Hyunju A1 - Steffen, Lyn M A1 - van Westing, Anniek C A1 - Geleijnse, Johanna M A1 - Hoogeveen, Ellen K A1 - Chen, Yun-Yu A1 - Chien, Kuo-Liong A1 - Fretts, Amanda M A1 - Lemaitre, Rozenn N A1 - Imamura, Fumiaki A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Birukov, Anna A1 - Jäger, Susanne A1 - Kuxhaus, Olga A1 - Schulze, Matthias B A1 - de Mello, Vanessa Derenji A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Lindström, Jaana A1 - Tintle, Nathan A1 - Harris, William S A1 - Yamasaki, Keisuke A1 - Hirakawa, Yoichiro A1 - Ninomiya, Toshiharu A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Virtanen, Jyrki K A1 - Voutilainen, Ari A1 - Jayasena, Tharusha A1 - Thalamuthu, Anbupalam A1 - Poljak, Anne A1 - Bustamante, Sonia A1 - Sachdev, Perminder S A1 - Senn, Mackenzie K A1 - Rich, Stephen S A1 - Tsai, Michael Y A1 - Wood, Alexis C A1 - Laakso, Markku A1 - Lankinen, Maria A1 - Yang, Xiaowei A1 - Sun, Liang A1 - Li, Huaixing A1 - Lin, Xu A1 - Nowak, Christoph A1 - Arnlöv, Johan A1 - Riserus, Ulf A1 - Lind, Lars A1 - Le Goff, Mélanie A1 - Samieri, Cecilia A1 - Helmer, Catherine A1 - Qian, Frank A1 - Micha, Renata A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Mozaffarian, Dariush A1 - Wu, Jason HY KW - alpha-Linolenic Acid KW - Fatty Acids, Omega-3 KW - Fatty Acids, Unsaturated KW - Humans KW - Middle Aged KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

OBJECTIVE: 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.

VL - 380 ER - TY - JOUR T1 - Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease. JF - JAMA Cardiol Y1 - 2023 A1 - Dron, Jacqueline S A1 - Patel, Aniruddh P A1 - Zhang, Yiyi A1 - Jurgens, Sean J A1 - Maamari, Dimitri J A1 - Wang, Minxian A1 - Boerwinkle, Eric A1 - Morrison, Alanna C A1 - de Vries, Paul S A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Bis, Joshua C A1 - Vasan, Ramachandran S A1 - Levy, Daniel A1 - Heard-Costa, Nancy A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Gibbs, Richard A A1 - Rotter, Jerome I A1 - Willer, Cristen J A1 - Oelsner, Elizabeth C A1 - Moran, Andrew E A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Khera, Amit V AB -

IMPORTANCE: 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.

ER - TY - JOUR T1 - Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. JF - Circulation Y1 - 2023 A1 - Zhang, Yiyi A1 - Dron, Jacqueline S A1 - Bellows, Brandon K A1 - Khera, Amit V A1 - Liu, Junxiu A1 - Balte, Pallavi P A1 - Oelsner, Elizabeth C A1 - Amr, Sami Samir A1 - Lebo, Matthew S A1 - Nagy, Anna A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Rotter, Jerome I A1 - Willer, Cristen A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Lutsey, Pamela L A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Floyd, James S A1 - Vasan, Ramachandran S A1 - Heard-Costa, Nancy L A1 - Carson, April P A1 - Hall, Michael E A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Kazi, Dhruv S A1 - de Ferranti, Sarah D A1 - Moran, Andrew E KW - Coronary Disease KW - Genotype KW - Humans KW - Hypercholesterolemia KW - Hyperlipoproteinemia Type II VL - 147 IS - 20 ER - TY - JOUR T1 - {Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors JF - JAMA Netw Open Y1 - 2023 A1 - Levine, D. A. A1 - Chen, B. A1 - Galecki, A. T. A1 - Gross, A. L. A1 - o, E. M. A1 - Whitney, R. T. A1 - Ploutz-Snyder, R. J. A1 - Giordani, B. J. A1 - Sussman, J. B. A1 - Burke, J. F. A1 - Lazar, R. M. A1 - Howard, V. J. A1 - Aparicio, H. J. A1 - Beiser, A. S. A1 - Elkind, M. S. V. A1 - Gottesman, R. F. A1 - Koton, S. A1 - Pendlebury, S. T. A1 - Sharma, A. A1 - Springer, M. V. A1 - Seshadri, S. A1 - Romero, J. R. A1 - Hayward, R. A. AB - Incident 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. VL - 6 ER - TY - JOUR T1 - Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study. JF - Kidney360 Y1 - 2023 A1 - Mehta, Rupal A1 - Bůzková, Petra A1 - Patel, Harnish A1 - Cheng, Jeanette A1 - Kizer, Jorge R A1 - Gottdiener, John S A1 - Psaty, Bruce A1 - Khan, Sadiya S A1 - Ix, Joachim H A1 - Isakova, Tamara A1 - Shlipak, Michael G A1 - Bansal, Nisha A1 - Shah, Sanjiv J AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. JF - medRxiv Y1 - 2023 A1 - Georgakis, Marios K A1 - Malik, Rainer A1 - Hasbani, Natalie R A1 - Shakt, Gabrielle A1 - Morrison, Alanna C A1 - Tsao, Noah L A1 - Judy, Renae A1 - Mitchell, Braxton D A1 - Xu, Huichun A1 - Montasser, May E A1 - Do, Ron A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Terry, James G A1 - Carr, John Jeffrey A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Young, Kendra A A1 - Lutz, Sharon M A1 - Cho, Michael H A1 - Broome, Jai A1 - Khan, Alyna T A1 - Wang, Fei Fei A1 - Heard-Costa, Nancy A1 - Seshadri, Sudha A1 - Vasan, Ramachandran S A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Yanek, Lisa R A1 - Kral, Brian G A1 - Becker, Lewis C A1 - Peyser, Patricia A A1 - Bielak, Lawrence F A1 - Ammous, Farah A1 - Carson, April P A1 - Hall, Michael E A1 - Raffield, Laura M A1 - Rich, Stephen S A1 - Post, Wendy S A1 - Tracy, Russel P A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Mahaney, Michael C A1 - Curran, Joanne E A1 - Blangero, John A1 - Clarke, Shoa L A1 - Haessler, Jeffrey W A1 - Hu, Yao A1 - Assimes, Themistocles L A1 - Kooperberg, Charles A1 - Damrauer, Scott M A1 - Rotter, Jerome I A1 - de Vries, Paul S A1 - Dichgans, Martin AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study. JF - Endocrinol Diabetes Metab Y1 - 2023 A1 - Olson, Nels C A1 - Doyle, Margaret F A1 - Bůzková, Petra A1 - Huber, Sally A A1 - de Boer, Ian H A1 - Sitlani, Colleen M A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Mukamal, Kenneth J A1 - Delaney, Joseph A KW - CD28 Antigens KW - CD8-Positive T-Lymphocytes KW - Cellular Senescence KW - Diabetes Mellitus KW - Leukocytes, Mononuclear KW - Lymphocyte Subsets AB -

INTRODUCTION: 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.

VL - 6 IS - 1 ER - TY - JOUR T1 - Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders. JF - J Gerontol A Biol Sci Med Sci Y1 - 2023 A1 - Kizer, Jorge R A1 - Patel, Sheena A1 - Ganz, Peter A1 - Newman, Anne B A1 - Bhasin, Shalender A1 - Lee, Se-Jin A1 - Cawthon, Peggy M A1 - LeBrasseur, Nathan A1 - Shah, Sanjiv J A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Cummings, Steven R AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults. JF - J Alzheimers Dis Y1 - 2023 A1 - de Oliveira Otto, Marcia C A1 - Wu, Jason H Y A1 - Thacker, Evan L A1 - Lai, Heidi Tsz Mung A1 - Lemaitre, Rozenn N A1 - Padhye, Nikhil A1 - Song, Xiaoling A1 - King, Irena B A1 - Lopez, Oscar A1 - Siscovick, David S A1 - Mozaffarian, Dariush AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Clonal hematopoiesis is associated with protection from Alzheimer's disease. JF - Nat Med Y1 - 2023 A1 - Bouzid, Hind A1 - Belk, Julia A A1 - Jan, Max A1 - Qi, Yanyan A1 - Sarnowski, Chloe A1 - Wirth, Sara A1 - Ma, Lisa A1 - Chrostek, Matthew R A1 - Ahmad, Herra A1 - Nachun, Daniel A1 - Yao, Winnie A1 - Beiser, Alexa A1 - Bick, Alexander G A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Longstreth, William T A1 - Lopez, Oscar L A1 - Natarajan, Pradeep A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Weinstock, Joshua A1 - Larson, Eric B A1 - Crane, Paul K A1 - Keene, C Dirk A1 - Seshadri, Sudha A1 - Satpathy, Ansuman T A1 - Montine, Thomas J A1 - Jaiswal, Siddhartha AB -

Clonal 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.

VL - 29 IS - 7 ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk. JF - Diabetes Care Y1 - 2023 A1 - Tobias, Deirdre K A1 - Manning, Alisa K A1 - Wessel, Jennifer A1 - Raghavan, Sridharan A1 - Westerman, Kenneth E A1 - Bick, Alexander G A1 - DiCorpo, Daniel A1 - Whitsel, Eric A A1 - Collins, Jason A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Dupuis, Josée A1 - Goodarzi, Mark O A1 - Guo, Xiuqing A1 - Howard, Barbara A1 - Lange, Leslie A A1 - Liu, Simin A1 - Raffield, Laura M A1 - Reiner, Alex P A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Tinker, Lesley A1 - Wilson, James G A1 - Wu, Peitao A1 - Carson, April P A1 - Vasan, Ramachandran S A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Rotter, Jerome I A1 - Meigs, James A1 - Manson, JoAnn E AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury. JF - medRxiv Y1 - 2023 A1 - Vlasschaert, Caitlyn A1 - Robinson-Cohen, Cassianne A1 - Kestenbaum, Bryan A1 - Silver, Samuel A A1 - Chen, Jian-Chun A1 - Akwo, Elvis A1 - Bhatraju, Pavan K A1 - Zhang, Ming-Zhi A1 - Cao, Shirong A1 - Jiang, Ming A1 - Wang, Yinqiu A1 - Niu, Aolei A1 - Siew, Edward A1 - Kramer, Holly J A1 - Köttgen, Anna A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Coresh, Josef A1 - Ballantyne, Christie M A1 - Boerwinkle, Eric A1 - Grams, Morgan A1 - Lanktree, Matthew B A1 - Rauh, Michael J A1 - Harris, Raymond C A1 - Bick, Alexander G AB -

Age 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.

ER - TY - JOUR T1 - CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk. JF - JAMA Netw Open Y1 - 2023 A1 - Huque, Md Hamidul A1 - Kootar, Scherazad A1 - Eramudugolla, Ranmalee A1 - Han, S Duke A1 - Carlson, Michelle C A1 - Lopez, Oscar L A1 - Bennett, David A A1 - Peters, Ruth A1 - Anstey, Kaarin J KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Australia KW - Cohort Studies KW - Female KW - Heart Disease Risk Factors KW - Humans KW - Male KW - Risk Factors AB -

IMPORTANCE: 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.

VL - 6 IS - 8 ER - TY - JOUR T1 - Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. JF - medRxiv Y1 - 2023 A1 - Sargurupremraj, Muralidharan A1 - Soumaré, Aïcha A1 - Bis, Joshua C A1 - Surakka, Ida A1 - Jürgenson, Tuuli A1 - Joly, Pierre A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Yang, Qiong A1 - Satizabal, Claudia L A1 - Gudjonsson, Alexander A1 - Mishra, Aniket A1 - Bouteloup, Vincent A1 - Phuah, Chia-Ling A1 - van Duijn, Cornelia M A1 - Cruchaga, Carlos A1 - Dufouil, Carole A1 - Chene, Geneviève A1 - Lopez, Oscar A1 - Psaty, Bruce M A1 - Tzourio, Christophe A1 - Amouyel, Philippe A1 - Adams, Hieab H A1 - Jacqmin-Gadda, Hélène A1 - Ikram, Mohammad Arfan A1 - Gudnason, Vilmundur A1 - Milani, Lili A1 - Winsvold, Bendik S A1 - Hveem, Kristian A1 - Matthews, Paul M A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Debette, Stephanie AB -

IMPORTANCE: 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.

ER - TY - JOUR T1 - Determinants of mosaic chromosomal alteration fitness. JF - medRxiv Y1 - 2023 A1 - Pershad, Yash A1 - Mack, Taralynn A1 - Poisner, Hannah A1 - Jakubek, Yasminka A A1 - Stilp, Adrienne M A1 - Mitchell, Braxton D A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Loos, Ruth J A1 - Chami, Nathalie A1 - Wang, Zhe A1 - Barnes, Kathleen A1 - Pankratz, Nathan A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Shojaie, Ali A1 - Silverman, Edwin K A1 - Cho, Michael H A1 - Yun, Jeong A1 - DeMeo, Dawn A1 - Levy, Daniel A1 - Johnson, Andrew A1 - Mathias, Rasika A1 - Taub, Margaret A1 - Arnett, Donna A1 - North, Kari A1 - Raffield, Laura M A1 - Carson, April A1 - Doyle, Margaret F A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Guo, Xiuqing A1 - Cox, Nancy A1 - Roden, Dan M A1 - Franceschini, Nora A1 - Desai, Pinkal A1 - Reiner, Alex A1 - Auer, Paul L A1 - Scheet, Paul A1 - Jaiswal, Siddhartha A1 - Weinstock, Joshua S A1 - Bick, Alexander G AB -

Clonal 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.

ER - TY - JOUR T1 - Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort. JF - J Am Coll Cardiol Y1 - 2023 A1 - Mohebi, Reza A1 - Wang, Dongyu A1 - Lau, Emily S A1 - Parekh, Juhi K A1 - Allen, Norrina A1 - Psaty, Bruce M A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Wang, Thomas J A1 - Shah, Sanjiv J A1 - Gottdiener, John S A1 - Januzzi, James L A1 - Ho, Jennifer E KW - American Heart Association KW - Atherosclerosis KW - Cardiology KW - Female KW - Heart Failure KW - Humans KW - Longitudinal Studies KW - Prognosis KW - United States AB -

BACKGROUND: 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.

VL - 81 IS - 23 ER - TY - JOUR T1 - Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS. JF - J Am Heart Assoc Y1 - 2023 A1 - Niezen, Sebastian A1 - Connelly, Margery A A1 - Hirsch, Calvin A1 - Kizer, Jorge R A1 - Benitez, Maria E A1 - Minchenberg, Scott A1 - Perez-Matos, Maria Camila A1 - Jiang, Zhenghui Gordon A1 - Mukamal, Kenneth J KW - Aged KW - Aging KW - Cardiovascular Diseases KW - Heart Failure KW - Humans KW - Incidence KW - Ketone Bodies AB -

Background 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.

VL - 12 IS - 17 ER - TY - JOUR T1 - Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. JF - Nat Commun Y1 - 2023 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Khan, Alyna T A1 - Wang, Jiongming A1 - Feofanova, Elena A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Kelly, Tanika A1 - Elfassy, Tali A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Lin, Henry J A1 - Hwang, Shih-Jen A1 - Gao, Yan A1 - Young, Kendra A1 - Kinney, Gregory L A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Zhu, Xiaofeng A1 - Chen, Yii-Der Ida A1 - Lee, I-Te A1 - Gu, C Charles A1 - Lloyd-Jones, Donald M A1 - Zöllner, Sebastian A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - Correa, Adolfo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Isasi, Carmen R A1 - Rich, Stephen S A1 - Kaplan, Robert C A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Morrison, Alanna C A1 - Sofer, Tamar KW - Blood Pressure KW - Ethnicity KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Multifactorial Inheritance KW - Population Health KW - Risk Factors AB -

We 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.

VL - 14 IS - 1 ER - TY - JOUR T1 - Evaluation 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. JF - J Gerontol A Biol Sci Med Sci Y1 - 2023 A1 - Newman, Anne B A1 - Patel, Sheena A1 - Kizer, Jorge A1 - Lee, Se-Jin A1 - Bhasin, Shalinder A1 - Cawthon, Peggy A1 - LeBrasseur, Nathan A1 - Tracy, Russel P A1 - Ganz, Peter A1 - Cummings, Steve AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. JF - Front Genet Y1 - 2023 A1 - de Las Fuentes, Lisa A1 - Schwander, Karen L A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Winkler, Thomas W A1 - Sung, Yun Ju A1 - Munroe, Patricia B A1 - Miller, Clint L A1 - Aschard, Hugo A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chai, Jin Fang A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Feitosa, Mary F A1 - Guo, Xiuqing A1 - Hartwig, Fernando P A1 - Horimoto, Andrea A1 - Kolcic, Ivana A1 - Lim, Elise A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Noordam, Raymond A1 - Padmanabhan, Sandosh A1 - Rankinen, Tuomo A1 - Richard, Melissa A A1 - Ridker, Paul M A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Zonderman, Alan B A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Christensen, Kaare A1 - Freedman, Barry I A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhan, Yiqiang A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chai, Xiaoran A1 - Chen, Yii-Der Ida A1 - Chen, Xu A1 - Chitrala, Kumaraswamy Naidu A1 - Concas, Maria Pina A1 - de Faire, Ulf A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Do, Ahn A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Floyd, James S A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Girotto, Giorgia A1 - Gu, C Charles A1 - Hallmans, Göran A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Homuth, Georg A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Langefeld, Carl D A1 - Liang, Jingjing A1 - Liu, Kiang A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pereira, Alexandre C A1 - Perls, Thomas A1 - Peters, Annette A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Sabanayagam, Charumathi A1 - Schreiner, Pamela J A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bonnefond, Amélie A1 - Bowden, Donald W A1 - Cooper, Richard S A1 - Deary, Ian J A1 - Divers, Jasmin A1 - Esko, Tõnu A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Penninx, Brenda A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Spedicati, Beatrice A1 - van der Harst, Pim A1 - Völzke, Henry A1 - Wagenknecht, Lynne E A1 - Weir, David R A1 - Wojczynski, Mary K A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Chasman, Daniel I A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Krieger, Jose Eduardo A1 - Mook-Kanamori, Dennis O A1 - Peyser, Patricia A A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Rudan, Igor A1 - Sim, Xueling A1 - Smith, Blair H A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Arnett, Donna K A1 - Rao, Dabeeru C A1 - Gauderman, James A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Fornage, Myriam AB -

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.

VL - 14 ER - TY - JOUR T1 - Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. JF - Nat Commun Y1 - 2023 A1 - Young, William J A1 - Haessler, Jeffrey A1 - Benjamins, Jan-Walter A1 - Repetto, Linda A1 - Yao, Jie A1 - Isaacs, Aaron A1 - Harper, Andrew R A1 - Ramirez, Julia A1 - Garnier, Sophie A1 - Van Duijvenboden, Stefan A1 - Baldassari, Antoine R A1 - Concas, Maria Pina A1 - Duong, ThuyVy A1 - Foco, Luisa A1 - Isaksen, Jonas L A1 - Mei, Hao A1 - Noordam, Raymond A1 - Nursyifa, Casia A1 - Richmond, Anne A1 - Santolalla, Meddly L A1 - Sitlani, Colleen M A1 - Soroush, Negin A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Aeschbacher, Stefanie A1 - Ahmadizar, Fariba A1 - Alonso, Alvaro A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Correa, Adolfo A1 - Darbar, Dawood A1 - De Luca, Antonio A1 - Deleuze, Jean-Francois A1 - Ellervik, Christina A1 - Fuchsberger, Christian A1 - Goel, Anuj A1 - Grace, Christopher A1 - Guo, Xiuqing A1 - Hansen, Torben A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Kors, Jan A A1 - Lima-Costa, Maria Fernanda A1 - Linneberg, Allan A1 - Macfarlane, Peter W A1 - Morrison, Alanna C A1 - Navarro, Pau A1 - Porteous, David J A1 - Pramstaller, Peter P A1 - Reiner, Alexander P A1 - Risch, Lorenz A1 - Schotten, Ulrich A1 - Shen, Xia A1 - Sinagra, Gianfranco A1 - Soliman, Elsayed Z A1 - Stoll, Monika A1 - Tarazona-Santos, Eduardo A1 - Tinker, Andrew A1 - Trajanoska, Katerina A1 - Villard, Eric A1 - Warren, Helen R A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Arking, Dan E A1 - Avery, Christy L A1 - Conen, David A1 - Girotto, Giorgia A1 - Grarup, Niels A1 - Hayward, Caroline A1 - Jukema, J Wouter A1 - Mook-Kanamori, Dennis O A1 - Olesen, Morten Salling A1 - Padmanabhan, Sandosh A1 - Psaty, Bruce M A1 - Pattaro, Cristian A1 - Ribeiro, Antonio Luiz P A1 - Rotter, Jerome I A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Wilson, James G A1 - Orini, Michele A1 - Charron, Philippe A1 - Watkins, Hugh A1 - Kooperberg, Charles A1 - Lin, Henry J A1 - Wilson, James F A1 - Kanters, Jørgen K A1 - Sotoodehnia, Nona A1 - Mifsud, Borbala A1 - Lambiase, Pier D A1 - Tereshchenko, Larisa G A1 - Munroe, Patricia B KW - Arrhythmias, Cardiac KW - Atrioventricular Block KW - Biomarkers KW - Cardiovascular Diseases KW - Electrocardiography KW - Genome-Wide Association Study KW - Humans KW - Risk Factors AB -

The 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.

VL - 14 IS - 1 ER - TY - JOUR T1 - Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. JF - bioRxiv Y1 - 2023 A1 - Einson, Jonah A1 - Glinos, Dafni A1 - Boerwinkle, Eric A1 - Castaldi, Peter A1 - Darbar, Dawood A1 - de Andrade, Mariza A1 - Ellinor, Patrick A1 - Fornage, Myriam A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A1 - Hersh, Craig P A1 - Johnsen, Jill A1 - Kaplan, Robert A1 - Konkle, Barbara A A1 - Kooperberg, Charles A1 - Nassir, Rami A1 - Loos, Ruth J F A1 - Meyers, Deborah A A1 - Mitchell, Braxton D A1 - Psaty, Bruce A1 - Vasan, Ramachandran S A1 - Rich, Stephen S A1 - Rienstra, Michael A1 - Rotter, Jerome I A1 - Saferali, Aabida A1 - Shoemaker, M Benjamin A1 - Silverman, Edwin A1 - Smith, Albert Vernon A1 - Mohammadi, Pejman A1 - Castel, Stephane E A1 - Iossifov, Ivan A1 - Lappalainen, Tuuli AB -

Exonic 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.

ER - TY - JOUR T1 - The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. JF - Sci Adv Y1 - 2023 A1 - Weinstock, Joshua S A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Redline, Susan A1 - Cade, Brian E A1 - Gilliland, Frank D A1 - Chen, Zhanghua A1 - Gauderman, W James A1 - Kumar, Rajesh A1 - Grammer, Leslie A1 - Schleimer, Robert P A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Weiss, Scott T A1 - Lasky-Su, Jessica A1 - DeMeo, Dawn L A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - Vasan, Ramachandran S A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon A1 - He, Jiang A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Manichaikul, Ani W A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - Gui, Hongsheng A1 - Xiao, Shujie A1 - Williams, L Keoki A1 - Meyers, Deborah A A1 - Li, Xingnan A1 - Ortega, Victor A1 - McGarvey, Stephen A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Desai, Pinkal A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Mathias, Rasika A1 - Natarajan, Pradeep A1 - Jaiswal, Siddhartha A1 - Reiner, Alexander P A1 - Bick, Alexander G KW - Germ-Line Mutation KW - Hematopoiesis KW - Humans KW - Middle Aged KW - Mutation KW - Mutation, Missense KW - Phenotype AB -

Nononcogenic 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.

VL - 9 IS - 17 ER - TY - JOUR T1 - Genome-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. JF - Res Sq Y1 - 2023 A1 - Yang, Chaojie A1 - Veenstra, Jenna A1 - Bartz, Traci A1 - Pahl, Matthew A1 - Hallmark, Brian A1 - Chen, Yii-Der Ida A1 - Westra, Jason A1 - Steffen, Lyn A1 - Brown, Christopher A1 - Siscovick, David A1 - Tsai, Michael A1 - Wood, Alexis A1 - Rich, Stephen A1 - Smith, Caren A1 - O'Connor, Timothy A1 - Mozaffarian, Dariush A1 - Grant, Struan A1 - Chilton, Floyd A1 - Tintle, Nathan A1 - Lemaitre, Rozenn A1 - Manichaikul, Ani AB -

Omega-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.

ER - TY - JOUR T1 - Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure. JF - medRxiv Y1 - 2023 A1 - Guirette, Melanie A1 - Lan, Jessie A1 - McKeown, Nicola A1 - Brown, Michael R A1 - Chen, Han A1 - de Vries, Paul S A1 - Kim, Hyunju A1 - Rebholz, Casey M A1 - Morrison, Alanna C A1 - Bartz, Traci M A1 - Fretts, Amanda M A1 - Guo, Xiuqing A1 - Lemaitre, Rozenn N A1 - Liu, Ching-Ti A1 - Noordam, Raymond A1 - de Mutsert, Renée A1 - Rosendaal, Frits R A1 - Wang, Carol A A1 - Beilin, Lawrence A1 - Mori, Trevor A A1 - Oddy, Wendy H A1 - Pennell, Craig E A1 - Chai, Jin Fang A1 - Whitton, Clare A1 - van Dam, Rob M A1 - Liu, Jianjun A1 - Tai, E Shyong A1 - Sim, Xueling A1 - Neuhouser, Marian L A1 - Kooperberg, Charles A1 - Tinker, Lesley A1 - Franceschini, Nora A1 - Huan, Tianxiao A1 - Winkler, Thomas W A1 - Bentley, Amy R A1 - Gauderman, W James A1 - Heerkens, Luc A1 - Tanaka, Toshiko A1 - van Rooij, Jeroen A1 - Munroe, Patricia B A1 - Warren, Helen R A1 - Voortman, Trudy A1 - Chen, Honglei A1 - Rao, D C A1 - Levy, Daniel A1 - Ma, Jiantao AB -

OBJECTIVE: 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.

ER - TY - JOUR T1 - {Identification of circulating proteins associated with general cognitive function among middle-aged and older adults JF - Commun Biol Y1 - 2023 A1 - Tin, A. A1 - Fohner, A. E. A1 - Yang, Q. A1 - Brody, J. A. A1 - Davies, G. A1 - Yao, J. A1 - Liu, D. A1 - Caro, I. A1 - Lindbohm, J. V. A1 - Duggan, M. R. A1 - Meirelles, O. A1 - Harris, S. E. A1 - Gudmundsdottir, V. A1 - Taylor, A. M. A1 - Henry, A. A1 - Beiser, A. S. A1 - Shojaie, A. A1 - Coors, A. A1 - Fitzpatrick, A. L. A1 - Langenberg, C. A1 - Satizabal, C. L. A1 - Sitlani, C. M. A1 - Wheeler, E. A1 - Tucker-Drob, E. M. A1 - Bressler, J. A1 - Coresh, J. A1 - Bis, J. C. A1 - Candia, J. A1 - Jennings, L. L. A1 - Pietzner, M. A1 - Lathrop, M. A1 - Lopez, O. L. A1 - Redmond, P. A1 - Gerszten, R. E. A1 - Rich, S. S. A1 - Heckbert, S. R. A1 - Austin, T. R. A1 - Hughes, T. M. A1 - Tanaka, T. A1 - Emilsson, V. A1 - Vasan, R. S. A1 - Guo, X. A1 - Zhu, Y. A1 - Tzourio, C. A1 - Rotter, J. I. A1 - Walker, K. A. A1 - Ferrucci, L. A1 - ki, M. A1 - Breteler, M. M. B. A1 - Cox, S. R. A1 - Debette, S. A1 - Mosley, T. H. A1 - Gudnason, V. G. A1 - Launer, L. J. A1 - Psaty, B. M. A1 - Seshadri, S. A1 - Fornage, M. AB - 2.0E-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. VL - 6 ER - TY - JOUR T1 - Inflammation and Incident Conduction Disease. JF - J Am Heart Assoc Y1 - 2023 A1 - Frimodt-Møller, Emilie K A1 - Gottdiener, John S A1 - Soliman, Elsayed Z A1 - Kizer, Jorge R A1 - Vittinghoff, Eric A1 - Psaty, Bruce M A1 - Biering-Sørensen, Tor A1 - Marcus, Gregory M KW - Cardiac Conduction System Disease KW - Electrocardiography KW - Heart Block KW - Humans KW - Inflammation VL - 12 IS - 1 ER - TY - JOUR T1 - Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis. JF - Aging Cell Y1 - 2023 A1 - Liu, Fangyu A1 - Austin, Thomas R A1 - Schrack, Jennifer A A1 - Chen, Jingsha A1 - Walston, Jeremy A1 - Mathias, Rasika A A1 - Grams, Morgan A1 - Odden, Michelle C A1 - Newman, Anne A1 - Psaty, Bruce M A1 - Ramonfaur, Diego A1 - Shah, Amil M A1 - Windham, B Gwen A1 - Coresh, Josef A1 - Walker, Keenan A AB -

Proteomic 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.

ER - TY - JOUR T1 - Lifestyle habits associated with cardiac conduction disease. JF - Eur Heart J Y1 - 2023 A1 - Frimodt-Møller, Emilie K A1 - Soliman, Elsayed Z A1 - Kizer, Jorge R A1 - Vittinghoff, Eric A1 - Psaty, Bruce M A1 - Biering-Sørensen, Tor A1 - Gottdiener, John S A1 - Marcus, Gregory M AB -

AIMS: 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.

ER - TY - JOUR T1 - loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology JF - medRxiv Y1 - 2023 A1 - Chemparathy, A. A1 - Guen, Y. L. A1 - Chen, S. A1 - Lee, E. G. A1 - Leong, L. A1 - Gorzynski, J. A1 - Xu, G. A1 - Belloy, M. A1 - Kasireddy, N. A1 - Tauber, A. P. A1 - Williams, K. A1 - Stewart, I. A1 - Wingo, T. A1 - Lah, J. A1 - Jayadev, S. A1 - Hales, C. A1 - Peskind, E. A1 - Child, D. D. A1 - Keene, C. D. A1 - Cong, L. A1 - Ashley, E. A1 - Yu, C. E. A1 - Greicius, M. D. AB - 4 or its protein product as a viable therapeutic option. ER - TY - JOUR T1 - Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores. JF - medRxiv Y1 - 2023 A1 - Hrytsenko, Yana A1 - Shea, Benjamin A1 - Elgart, Michael A1 - Kurniansyah, Nuzulul A1 - Lyons, Genevieve A1 - Morrison, Alanna C A1 - Carson, April P A1 - Haring, Bernhard A1 - Mitchel, Braxton D A1 - Psaty, Bruce M A1 - Jaeger, Byron C A1 - Gu, C Charles A1 - Kooperberg, Charles A1 - Levy, Daniel A1 - Lloyd-Jones, Donald A1 - Choi, Eunhee A1 - Brody, Jennifer A A1 - Smith, Jennifer A A1 - Rotter, Jerome I A1 - Moll, Matthew A1 - Fornage, Myriam A1 - Simon, Noah A1 - Castaldi, Peter A1 - Casanova, Ramon A1 - Chung, Ren-Hua A1 - Kaplan, Robert A1 - Loos, Ruth J F A1 - Kardia, Sharon L R A1 - Rich, Stephen S A1 - Redline, Susan A1 - Kelly, Tanika A1 - O'Connor, Timothy A1 - Zhao, Wei A1 - Kim, Wonji A1 - Guo, Xiuqing A1 - Der Ida Chen, Yii A1 - Sofer, Tamar AB -

We 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.

ER - TY - JOUR T1 - Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. JF - Nat Genet Y1 - 2023 A1 - Jakubek, Yasminka A A1 - Zhou, Ying A1 - Stilp, Adrienne A1 - Bacon, Jason A1 - Wong, Justin W A1 - Ozcan, Zuhal A1 - Arnett, Donna A1 - Barnes, Kathleen A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Jiawen A1 - Cho, Michael A1 - Conomos, Matthew P A1 - Cox, Nancy A1 - Doyle, Margaret F A1 - Fornage, Myriam A1 - Guo, Xiuqing A1 - Kardia, Sharon L R A1 - Lewis, Joshua P A1 - Loos, Ruth J F A1 - Ma, Xiaolong A1 - Machiela, Mitchell J A1 - Mack, Taralynn M A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mychaleckyj, Josyf C A1 - North, Kari A1 - Pankratz, Nathan A1 - Peyser, Patricia A A1 - Preuss, Michael H A1 - Psaty, Bruce A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Silverman, Edwin K A1 - Smith, Jennifer A A1 - Smith, Aaron P A1 - Taub, Margaret A1 - Taylor, Kent D A1 - Yun, Jeong A1 - Li, Yun A1 - Desai, Pinkal A1 - Bick, Alexander G A1 - Reiner, Alexander P A1 - Scheet, Paul A1 - Auer, Paul L KW - Black People KW - Genome, Human KW - Genome-Wide Association Study KW - Hispanic or Latino KW - Humans KW - Mosaicism KW - Precision Medicine AB -

Megabase-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.

VL - 55 IS - 11 ER - TY - JOUR T1 - Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. JF - Nat Genet Y1 - 2023 A1 - Kavousi, Maryam A1 - Bos, Maxime M A1 - Barnes, Hanna J A1 - Lino Cardenas, Christian L A1 - Wong, Doris A1 - Lu, Haojie A1 - Hodonsky, Chani J A1 - Landsmeer, Lennart P L A1 - Turner, Adam W A1 - Kho, Minjung A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Bowden, Donald W A1 - Chopade, Sandesh A1 - Deelen, Joris A1 - Benavente, Ernest Diez A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Hwang, Shih-Jen A1 - Lutz, Sharon M A1 - Lyytikäinen, Leo-Pekka A1 - Slenders, Lotte A1 - Smith, Albert V A1 - Stanislawski, Maggie A A1 - van Setten, Jessica A1 - Wong, Quenna A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Beekman, Marian A1 - Budoff, Matthew J A1 - Feitosa, Mary F A1 - Finan, Chris A1 - Hilliard, Austin T A1 - Kardia, Sharon L R A1 - Kovacic, Jason C A1 - Kral, Brian G A1 - Langefeld, Carl D A1 - Launer, Lenore J A1 - Malik, Shaista A1 - Hoesein, Firdaus A A Mohamed A1 - Mokry, Michal A1 - Schmidt, Reinhold A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Terry, James G A1 - van der Grond, Jeroen A1 - van Meurs, Joyce A1 - Vliegenthart, Rozemarijn A1 - Xu, Jianzhao A1 - Young, Kendra A A1 - Zilhão, Nuno R A1 - Zweiker, Robert A1 - Assimes, Themistocles L A1 - Becker, Lewis C A1 - Bos, Daniel A1 - Carr, J Jeffrey A1 - Cupples, L Adrienne A1 - de Kleijn, Dominique P V A1 - de Winther, Menno A1 - den Ruijter, Hester M A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Hokanson, John E A1 - Ikram, M Arfan A1 - Išgum, Ivana A1 - Jacobs, David R A1 - Kähönen, Mika A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Pasterkamp, Gerard A1 - Raitakari, Olli T A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Bis, Joshua C A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Post, Wendy S A1 - Rotter, Jerome I A1 - Björkegren, Johan L M A1 - O'Donnell, Christopher J A1 - Bielak, Lawrence F A1 - Peyser, Patricia A A1 - Malhotra, Rajeev A1 - van der Laan, Sander W A1 - Miller, Clint L AB -

Coronary 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.

VL - 55 IS - 10 ER - TY - JOUR T1 - Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. JF - medRxiv Y1 - 2023 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Ana Luiza de, S V Arruda A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Alaine Broadaway, K A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - Janaka de Silva, H A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Gordon-Larsen, Penny A1 - Gross, Myron A1 - Guare, Lindsay A A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Horikoshi, Momoko A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lithgart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Project, Biobank Japan A1 - BioBank, Penn Medicine A1 - Center, Regeneron Genetics A1 - Consortium, eMERGE A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Geoffrey Hayes, M A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 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.

ER - TY - JOUR T1 - Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. JF - Nat Genet Y1 - 2023 A1 - Chen, Fang A1 - Wang, Xingyan A1 - Jang, Seon-Kyeong A1 - Quach, Bryan C A1 - Weissenkampen, J Dylan A1 - Khunsriraksakul, Chachrit A1 - Yang, Lina A1 - Sauteraud, Renan A1 - Albert, Christine M A1 - Allred, Nicholette D D A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Barr, R Graham A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boorgula, Meher Preethi A1 - Chasman, Daniel I A1 - Chavan, Sameer A1 - Chen, Yii-der I A1 - Chuang, Lee-Ming A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - David, Sean P A1 - Fuentes, Lisa de Las A1 - Deka, Ranjan A1 - Duggirala, Ravindranath A1 - Faul, Jessica D A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - Hawley, Nicola L A1 - He, Jiang A1 - Hobbs, Brian D A1 - Hokanson, John E A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Hyde, Thomas M A1 - Irvin, Marguerite R A1 - Jaffe, Andrew E A1 - Johnson, Eric O A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kaufman, Joel D A1 - Kelly, Tanika N A1 - Kleinman, Joel E A1 - Kooperberg, Charles A1 - Lee, I-Te A1 - Levy, Daniel A1 - Lutz, Sharon M A1 - Manichaikul, Ani W A1 - Martin, Lisa W A1 - Marx, Olivia A1 - McGarvey, Stephen T A1 - Minster, Ryan L A1 - Moll, Matthew A1 - Moussa, Karine A A1 - Naseri, Take A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Rafaels, Nicholas A1 - Raffield, Laura M A1 - Reupena, Muagututi'a Sefuiva A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Sheu, Wayne H-H A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sun, Xiao A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Watson, Harold A1 - Weeks, Daniel E A1 - Weir, David R A1 - Yanek, Lisa R A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhao, Wei A1 - Hancock, Dana B A1 - Jiang, Bibo A1 - Vrieze, Scott A1 - Liu, Dajiang J KW - Biology KW - Drug Repositioning KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Tobacco Use KW - Transcriptome AB -

Most 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.

VL - 55 IS - 2 ER - TY - JOUR T1 - Multiple Prior Live Births are Associated with Cardiac Remodeling and Heart Failure Risk in Women. JF - J Card Fail Y1 - 2023 A1 - Sarma, Amy A A1 - Paniagua, Samantha M A1 - Lau, Emily S A1 - Wang, Dongyu A1 - Liu, Elizabeth E A1 - Larson, Martin G A1 - Hamburg, Naomi M A1 - Mitchell, Gary F A1 - Kizer, Jorge A1 - Psaty, Bruce M A1 - Allen, Norrina B A1 - Lely, A Titia A1 - Gansevoort, Ronald T A1 - Rosenberg, Emily A1 - Mukamal, Kenneth A1 - Benjamin, Emelia J A1 - Vasan, Ramachandran S A1 - Cheng, Susan A1 - Levy, Daniel A1 - de Boer, Rudolf A A1 - Gottdiener, John S A1 - Shah, Sanjiv J A1 - Ho, Jennifer E AB -

INTRODUCTION: 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.

ER - TY - JOUR T1 - Neighborhood greenspace and cognition: The cardiovascular health study. JF - Health Place Y1 - 2023 A1 - Godina, Sara L A1 - Rosso, Andrea L A1 - Hirsch, Jana A A1 - Besser, Lilah M A1 - Lovasi, Gina S A1 - Donovan, Geoffrey H A1 - Garg, Parveen K A1 - Platt, Jonathan M A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Carlson, Michelle C A1 - Michael, Yvonne L AB -

OBJECTIVES: 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.

VL - 79 ER - TY - JOUR T1 - Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study. JF - JAMA Netw Open Y1 - 2023 A1 - Bockus, Lee B A1 - Jensen, Paul N A1 - Fretts, Amanda M A1 - Hoofnagle, Andrew N A1 - McKnight, Barbara A1 - Sitlani, Colleen M A1 - Siscovick, David S A1 - King, Irena B A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Lemaitre, Rozenn N KW - Aged KW - Ceramides KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Eicosanoic Acids KW - Fatty Acids KW - Female KW - Humans KW - Male KW - Sphingolipids KW - Sphingomyelins AB -

IMPORTANCE: 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.

VL - 6 IS - 11 ER - TY - JOUR T1 - Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study. JF - Neurology Y1 - 2023 A1 - Kalani, Rizwan A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Elkind, Mitchell S V A1 - Floyd, James S A1 - Gerszten, Robert E A1 - Shojaie, Ali A1 - Heckbert, Susan R A1 - Bis, Joshua C A1 - Austin, Thomas R A1 - Tirschwell, David L A1 - Delaney, Joseph A C A1 - Longstreth, W T AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study. JF - ERJ Open Res Y1 - 2023 A1 - Gharib, Arya R A1 - Jensen, Paul N A1 - Psaty, Bruce M A1 - Hoofnagle, Andrew N A1 - Siscovick, David A1 - Gharib, Sina A A1 - Sitlani, Colleen M A1 - Sotoodehnia, Nona A1 - Lemaitre, Rozenn N AB -

RATIONALE: 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.

VL - 9 IS - 2 ER - TY - JOUR T1 - Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis. JF - J Am Heart Assoc Y1 - 2023 A1 - Lemaitre, Rozenn N A1 - Jensen, Paul N A1 - Wang, Zeneng A1 - Fretts, Amanda M A1 - Sitlani, Colleen M A1 - Nemet, Ina A1 - Sotoodehnia, Nona A1 - de Oliveira Otto, Marcia C A1 - Zhu, Weifei A1 - Budoff, Matt A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Hazen, Stanley L A1 - Mozaffarian, Dariush KW - Aged KW - Atherosclerosis KW - Female KW - Humans KW - Ischemic Stroke KW - Methylamines KW - Oxides KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

Background 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.

VL - 12 IS - 16 ER - TY - JOUR T1 - {Polygenic burden of short tandem repeat expansions promote risk for Alzheimer's disease JF - medRxiv Y1 - 2023 A1 - Guo, M. H. A1 - Lee, W. P. A1 - Vardarajan, B. A1 - Schellenberg, G. D. A1 - Phillips-Cremins, J. AB - 30 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. ER - TY - JOUR T1 - Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. JF - Nat Genet Y1 - 2023 A1 - Li, Xihao A1 - Quick, Corbin A1 - Zhou, Hufeng A1 - Gaynor, Sheila M A1 - Liu, Yaowu A1 - Chen, Han A1 - Selvaraj, Margaret Sunitha A1 - Sun, Ryan A1 - Dey, Rounak A1 - Arnett, Donna K A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Duggirala, Ravindranath A1 - Freedman, Barry I A1 - Göring, Harald H H A1 - Guo, Xiuqing A1 - Haessler, Jeffrey A1 - Kalyani, Rita R A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Martin, Lisa W A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Willer, Cristen J A1 - Wilson, James G A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Li, Zilin A1 - Lin, Xihong KW - Exome Sequencing KW - Genome-Wide Association Study KW - Lipids KW - Phenotype KW - Whole Genome Sequencing AB -

Meta-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.

VL - 55 IS - 1 ER - TY - JOUR T1 - Prediction of Multiple Individual Primary Cardiovascular Events Using Pooled Cohorts. JF - medRxiv Y1 - 2023 A1 - Sussman, Jeremy B A1 - Whitney, Rachael T A1 - Burke, James F A1 - Hayward, Rodney A A1 - Galecki, Andrzej A1 - Sidney, Stephen A1 - Allen, Norrina Bai A1 - Gottesman, Rebecca F A1 - Heckbert, Susan R A1 - Longstreth, William T A1 - Psaty, Bruce M A1 - Elkind, Mitchell S V A1 - Levine, Deborah A AB -

INTRODUCTION: 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.

ER - TY - JOUR T1 - A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study). JF - Europace Y1 - 2023 A1 - Jonmundsson, Thorarinn A1 - Steindorsdottir, Anna E A1 - Austin, Thomas R A1 - Frick, Elisabet A A1 - Axelsson, Gisli T A1 - Launer, Lenore A1 - Psaty, Bruce M A1 - Loureiro, Joseph A1 - Orth, Anthony P A1 - Aspelund, Thor A1 - Emilsson, Valur A1 - Floyd, James S A1 - Jennings, Lori A1 - Gudnason, Vilmundur A1 - Gudmundsdottir, Valborg KW - Atrial Fibrillation KW - Biomarkers KW - Endosomal Sorting Complexes Required for Transport KW - Humans KW - Natriuretic Peptide, Brain KW - Oxidoreductases Acting on Sulfur Group Donors KW - Peptide Fragments KW - Prognosis KW - Prospective Studies KW - Proteomics KW - Risk Factors AB -

AIMS: 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.

VL - 25 IS - 11 ER - TY - JOUR T1 - Proteomic prediction of incident heart failure and its main subtypes. JF - Eur J Heart Fail Y1 - 2023 A1 - Emilsson, Valur A1 - Jonsson, Brynjolfur G A1 - Austin, Thomas R A1 - Gudmundsdottir, Valborg A1 - Axelsson, Gisli T A1 - Frick, Elisabet A A1 - Jonmundsson, Thorarinn A1 - Steindorsdottir, Anna E A1 - Loureiro, Joseph A1 - Brody, Jennifer A A1 - Aspelund, Thor A1 - Launer, Lenore J A1 - Thorgeirsson, Gudmundur A1 - Kortekaas, Kirsten A A1 - Lindeman, Jan H A1 - Orth, Anthony P A1 - Lamb, John R A1 - Psaty, Bruce M A1 - Kizer, Jorge R A1 - Jennings, Lori L A1 - Gudnason, Vilmundur AB -

AIM: 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.

ER - TY - JOUR T1 - Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. JF - medRxiv Y1 - 2023 A1 - Wang, Yuxuan A1 - Selvaraj, Margaret Sunitha A1 - Li, Xihao A1 - Li, Zilin A1 - Holdcraft, Jacob A A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Cade, Brian E A1 - Carlson, Jenna C A1 - Carson, April P A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Floyd, James S A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Guo, Xiuqing A1 - He, Jiang A1 - Heard-Costa, Nancy A1 - Hildalgo, Bertha A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Joehanes, Roby A1 - Kaplan, Robert C A1 - Kardia, Sharon Lr A1 - Kelly, Tanika N A1 - Kim, Ryan A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Levy, Daniel A1 - Li, Changwei A1 - Liu, Chunyu A1 - Lloyd-Jone, Don A1 - Loos, Ruth Jf A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Ruepena, Muagututi'a Sefuiva A1 - Sheu, Wayne H-H A1 - Smith, Jennifer A A1 - Smith, Albert A1 - Tiwari, Hemant K A1 - Tsai, Michael Y A1 - Viaud-Martinez, Karine A A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Natarajan, Pradeep A1 - Peloso, Gina M AB -

Long 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.

ER - TY - JOUR T1 - {Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study JF - Alzheimers Dement Y1 - 2023 A1 - é, H. T. A1 - Liu, X. A1 - Odden, M. C. A1 - Moseholm, K. F. A1 - Seshadri, S. A1 - Satizabal, C. L. A1 - Lopez, O. L. A1 - Bis, J. C. A1 - é, L. A1 - Fohner, A. E. A1 - Psaty, B. M. A1 - Tracy, R. P. A1 - Longstreth, W. T. A1 - Jensen, M. K. A1 - Mukamal, K. J. AB - Circulating 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. ER - TY - JOUR T1 - Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults. JF - JAMA Netw Open Y1 - 2023 A1 - Pase, Matthew P A1 - Harrison, Stephanie A1 - Misialek, Jeffrey R A1 - Kline, Christopher E A1 - Cavuoto, Marina A1 - Baril, Andree-Ann A1 - Yiallourou, Stephanie A1 - Bisson, Alycia A1 - Himali, Dibya A1 - Leng, Yue A1 - Yang, Qiong A1 - Seshadri, Sudha A1 - Beiser, Alexa A1 - Gottesman, Rebecca F A1 - Redline, Susan A1 - Lopez, Oscar A1 - Lutsey, Pamela L A1 - Yaffe, Kristine A1 - Stone, Katie L A1 - Purcell, Shaun M A1 - Himali, Jayandra J AB -

IMPORTANCE: 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.

VL - 6 IS - 7 ER - TY - JOUR T1 - A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. JF - bioRxiv Y1 - 2023 A1 - Li, Xihao A1 - Chen, Han A1 - Selvaraj, Margaret Sunitha A1 - Van Buren, Eric A1 - Zhou, Hufeng A1 - Wang, Yuxuan A1 - Sun, Ryan A1 - McCaw, Zachary R A1 - Yu, Zhi A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Carson, April P A1 - Carlson, Jenna C A1 - Chami, Nathalie A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Gu, Charles A1 - Heard-Costa, Nancy L A1 - He, Jiang A1 - Hou, Lifang A1 - Hung, Yi-Jen A1 - Irvin, Marguerite R A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Konigsberg, Iain A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Li, Changwei A1 - Loos, Ruth J F A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Tiwari, Hemant A1 - Vasan, Ramachandran S A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Yu, Bing A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Li, Zilin A1 - Liu, Zhonghua A1 - Lin, Xihong AB -

Large-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.

ER - TY - JOUR T1 - Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. JF - medRxiv Y1 - 2023 A1 - Kwak, Soo Heon A1 - Hernandez-Cancela, Ryan B A1 - DiCorpo, Daniel A A1 - Condon, David E A1 - Merino, Jordi A1 - Wu, Peitao A1 - Brody, Jennifer A A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Ahmadizar, Fariba A1 - Meyer, Mariah A1 - Sincan, Murat A1 - Mercader, Josep M A1 - Lee, Sujin A1 - Haessler, Jeffrey A1 - Vy, Ha My T A1 - Lin, Zhaotong A1 - Armstrong, Nicole D A1 - Gu, Shaopeng A1 - Tsao, Noah L A1 - Lange, Leslie A A1 - Wang, Ningyuan A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Liu, Simin A1 - Loos, Ruth J F A1 - Judy, Renae A1 - Schroeder, Philip H A1 - Hasbani, Natalie R A1 - Bos, Maxime M A1 - Morrison, Alanna C A1 - Jackson, Rebecca D A1 - Reiner, Alexander P A1 - Manson, JoAnn E A1 - Chaudhary, Ninad S A1 - Carmichael, Lynn K A1 - Chen, Yii-Der Ida A1 - Taylor, Kent D A1 - Ghanbari, Mohsen A1 - van Meurs, Joyce A1 - Pitsillides, Achilleas N A1 - Psaty, Bruce M A1 - Noordam, Raymond A1 - Do, Ron A1 - Park, Kyong Soo A1 - Jukema, J Wouter A1 - Kavousi, Maryam A1 - Correa, Adolfo A1 - Rich, Stephen S A1 - Damrauer, Scott M A1 - Hajek, Catherine A1 - Cho, Nam H A1 - Irvin, Marguerite R A1 - Pankow, James S A1 - Nadkarni, Girish N A1 - Sladek, Robert A1 - Goodarzi, Mark O A1 - Florez, Jose C A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Dupuis, Josée A1 - Malhotra, Rajeev A1 - de Vries, Paul S A1 - Liu, Ching-Ti A1 - Rotter, Jerome I A1 - Meigs, James B AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults. JF - Heart Y1 - 2023 A1 - Massera, Daniele A1 - Bartz, Traci M A1 - Biggs, Mary L A1 - Sotoodehnia, Nona A1 - Reiner, Alexander P A1 - Semba, Richard D A1 - Gottdiener, John S A1 - Psaty, Bruce M A1 - Owens, David S A1 - Kizer, Jorge R AB -

OBJECTIVES: 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.

ER - TY - JOUR T1 - A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies. JF - J Endocr Soc Y1 - 2023 A1 - Srinivasan, Shylaja A1 - Wu, Peitao A1 - Mercader, Josep M A1 - Udler, Miriam S A1 - Porneala, Bianca C A1 - Bartz, Traci M A1 - Floyd, James S A1 - Sitlani, Colleen A1 - Guo, Xiquing A1 - Haessler, Jeffrey A1 - Kooperberg, Charles A1 - Liu, Jun A1 - Ahmad, Shahzad A1 - van Duijn, Cornelia A1 - Liu, Ching-Ti A1 - Goodarzi, Mark O A1 - Florez, Jose C A1 - Meigs, James B A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Dupuis, Josée A1 - Leong, Aaron AB -

CONTEXT: 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.

VL - 7 IS - 11 ER - TY - JOUR T1 - Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis. JF - Circ Genom Precis Med Y1 - 2023 A1 - Hasbani, Natalie R A1 - Westerman, Kenneth E A1 - Heon Kwak, Soo A1 - Chen, Han A1 - Li, Xihao A1 - DiCorpo, Daniel A1 - Wessel, Jennifer A1 - Bis, Joshua C A1 - Sarnowski, Chloe A1 - Wu, Peitao A1 - Bielak, Lawrence F A1 - Guo, Xiuqing A1 - Heard-Costa, Nancy A1 - Kinney, Gregory A1 - Mahaney, Michael C A1 - Montasser, May E A1 - Palmer, Nicholette D A1 - Raffield, Laura M A1 - Terry, James G A1 - Yanek, Lisa R A1 - Bon, Jessica A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Duggirala, Ravindranath A1 - Jacobs, David R A1 - Kalyani, Rita R A1 - Lange, Leslie A A1 - Mitchell, Braxton D A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Carson, April A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Gibbs, Richard A A1 - Gupta, Namrata A1 - Kardia, Sharon L R A1 - Kral, Brian G A1 - Momin, Zeineen A1 - Newman, Anne B A1 - Post, Wendy S A1 - Viaud-Martinez, Karine A A1 - Young, Kendra A A1 - Becker, Lewis C A1 - Bertoni, Alain A1 - Blangero, John A1 - Carr, John J A1 - Pratte, Katherine A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Wu, Joseph C A1 - Malhotra, Rajeev A1 - Peyser, Patricia A A1 - Morrison, Alanna C A1 - Vasan, Ramachandran S A1 - Lin, Xihong A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Manning, Alisa K A1 - de Vries, Paul S AB -

BACKGROUND: 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.

ER - TY - JOUR T1 - Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations. JF - J Prev Alzheimers Dis Y1 - 2023 A1 - Kootar, S A1 - Huque, M H A1 - Eramudugolla, R A1 - Rizzuto, D A1 - Carlson, M C A1 - Odden, M C A1 - Lopez, O L A1 - Qiu, C A1 - Fratiglioni, L A1 - Han, S D A1 - Bennett, D A A1 - Peters, R A1 - Anstey, K J KW - Aging KW - Alzheimer Disease KW - Cohort Studies KW - Dementia KW - Humans KW - Independent Living AB -

BACKGROUND: 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.

VL - 10 IS - 3 ER - TY - JOUR T1 - Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. JF - medRxiv Y1 - 2023 A1 - Huffman, Jennifer E A1 - Nicolas, Jayna A1 - Hahn, Julie A1 - Heath, Adam S A1 - Raffield, Laura M A1 - Yanek, Lisa R A1 - Brody, Jennifer A A1 - Thibord, Florian A1 - Almasy, Laura A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Bowler, Russell P A1 - Carrasquilla, Germán D A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Emmert, David B A1 - Ghanbari, Mohsen A1 - Haessle, Jeffery A1 - Hottenga, Jouke-Jan A1 - Kleber, Marcus E A1 - Le, Ngoc-Quynh A1 - Lee, Jiwon A1 - Lewis, Joshua P A1 - Li-Gao, Ruifang A1 - Luan, Jian'an A1 - Malmberg, Anni A1 - Mangino, Massimo A1 - Marioni, Riccardo E A1 - Martinez-Perez, Angel A1 - Pankratz, Nathan A1 - Polasek, Ozren A1 - Richmond, Anne A1 - Rodriguez, Benjamin At A1 - Rotter, Jerome I A1 - Steri, Maristella A1 - Suchon, Pierre A1 - Trompet, Stella A1 - Weiss, Stefan A1 - Zare, Marjan A1 - Auer, Paul A1 - Cho, Michael H A1 - Christofidou, Paraskevi A1 - Davies, Gail A1 - de Geus, Eco A1 - Deleuze, Jean-Francois A1 - Delgado, Graciela E A1 - Ekunwe, Lynette A1 - Faraday, Nauder A1 - Gögele, Martin A1 - Greinacher, Andreas A1 - He, Gao A1 - Howard, Tom A1 - Joshi, Peter K A1 - Kilpeläinen, Tuomas O A1 - Lahti, Jari A1 - Linneberg, Allan A1 - Naitza, Silvia A1 - Noordam, Raymond A1 - Paüls-Vergés, Ferran A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Ryan, Kathleen A A1 - Souto, Juan Carlos A1 - van Rooij, Frank Ja A1 - Wang, Heming A1 - Zhao, Wei A1 - Becker, Lewis C A1 - Beswick, Andrew A1 - Brown, Michael R A1 - Cade, Brian E A1 - Campbell, Harry A1 - Cho, Kelly A1 - Crapo, James D A1 - Curran, Joanne E A1 - de Maat, Moniek Pm A1 - Doyle, Margaret A1 - Elliott, Paul A1 - Floyd, James S A1 - Fuchsberger, Christian A1 - Grarup, Niels A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Hou, Lifang A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Menni, Cristina A1 - Nauck, Matthias A1 - O'Connell, Jeffrey R A1 - Orrù, Valeria A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Smith, Jennifer A A1 - Soria, José Manuel A1 - Stott, David J A1 - van Hylckama Vlieg, Astrid A1 - Watkins, Hugh A1 - Willemsen, Gonneke A1 - Wilson, Peter A1 - Ben-Shlomo, Yoav A1 - Blangero, John A1 - Boomsma, Dorret A1 - Cox, Simon R A1 - Dehghan, Abbas A1 - Eriksson, Johan G A1 - Fiorillo, Edoardo A1 - Fornage, Myriam A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon Lr A1 - Lange, Leslie A A1 - März, Winfried A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mook-Kanamori, Dennis O A1 - Morange, Pierre-Emmanuel A1 - Pedersen, Oluf A1 - Pramstaller, Peter P A1 - Redline, Susan A1 - Reiner, Alexander A1 - Ridker, Paul M A1 - Silverman, Edwin K A1 - Spector, Tim D A1 - Völker, Uwe A1 - Wareham, Nick A1 - Wilson, James F A1 - Yao, Jie A1 - Trégouët, David-Alexandre A1 - Johnson, Andrew D A1 - Wolberg, Alisa S A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Morrison, Alanna C A1 - Smith, Nicholas L AB -

UNLABELLED: 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.

ER - TY - JOUR T1 - Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. JF - Circ Genom Precis Med Y1 - 2023 A1 - Seyerle, Amanda A A1 - Laurie, Cecelia A A1 - Coombes, Brandon J A1 - Jain, Deepti A1 - Conomos, Matthew P A1 - Brody, Jennifer A1 - Chen, Ming-Huei A1 - Gogarten, Stephanie M A1 - Beutel, Kathleen M A1 - Gupta, Namrata A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Johnson, Andrew D A1 - Ko, Darae A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Metcalf, Ginger A A1 - Morrison, Alanna C A1 - Reiner, Alexander P A1 - Sofer, Tamar A1 - Tang, Weihong A1 - Wiggins, Kerri L A1 - Boerwinkle, Eric A1 - Andrade, Mariza de A1 - Gabriel, Stacey B A1 - Gibbs, Richard A A1 - Laurie, Cathy C A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Rice, Ken A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Smith, Nicholas L A1 - Pankratz, Nathan AB -

Background 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.

ER - TY - JOUR T1 - Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program. JF - Front Genet Y1 - 2023 A1 - Armstrong, Nicole D A1 - Srinivasasainagendra, Vinodh A1 - Ammous, Farah A1 - Assimes, Themistocles L A1 - Beitelshees, Amber L A1 - Brody, Jennifer A1 - Cade, Brian E A1 - Ida Chen, Yii-Der A1 - Chen, Han A1 - de Vries, Paul S A1 - Floyd, James S A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hellwege, Jacklyn N A1 - House, John S A1 - Hwu, Chii-Min A1 - Kardia, Sharon L R A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - McDonough, Caitrin W A1 - Montasser, May E A1 - O'Connell, Jeffrey R A1 - Shuey, Megan M A1 - Sun, Xiao A1 - Tanner, Rikki M A1 - Wang, Zhe A1 - Zhao, Wei A1 - Carson, April P A1 - Edwards, Todd L A1 - Kelly, Tanika N A1 - Kenny, Eimear E A1 - Kooperberg, Charles A1 - Loos, Ruth J F A1 - Morrison, Alanna C A1 - Motsinger-Reif, Alison A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Irvin, Marguerite R A1 - Arnett, Donna K AB -

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.

VL - 14 ER - TY - JOUR T1 - WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. JF - medRxiv Y1 - 2023 A1 - Zhang, Xinruo A1 - Brody, Jennifer A A1 - Graff, Mariaelisa A1 - Highland, Heather M A1 - Chami, Nathalie A1 - Xu, Hanfei A1 - Wang, Zhe A1 - Ferrier, Kendra A1 - Chittoor, Geetha A1 - Josyula, Navya S A1 - Li, Xihao A1 - Li, Zilin A1 - Allison, Matthew A A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Broome, Jai G A1 - Buth, Erin J A1 - Carlson, Christopher S A1 - Chang, Kyong-Mi A1 - Chavan, Sameer A1 - Chiu, Yen-Feng A1 - Chuang, Lee-Ming A1 - Conomos, Matthew P A1 - DeMeo, Dawn L A1 - Du, Margaret A1 - Duggirala, Ravindranath A1 - Eng, Celeste A1 - Fohner, Alison E A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Guo, Xiuqing A1 - Haiman, Chris A1 - Heavner, Benjamin D A1 - Hidalgo, Bertha A1 - Hixson, James E A1 - Ho, Yuk-Lam A1 - Hobbs, Brian D A1 - Hu, Donglei A1 - Hui, Qin A1 - Hwu, Chii-Min A1 - Jackson, Rebecca D A1 - Jain, Deepti A1 - Kalyani, Rita R A1 - Kardia, Sharon L R A1 - Kelly, Tanika N A1 - Lange, Ethan M A1 - LeNoir, Michael A1 - Li, Changwei A1 - Marchand, Loic Le A1 - McDonald, Merry-Lynn N A1 - McHugh, Caitlin P A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey A1 - O'Donnell, Christopher J A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Perry, James A A1 - Peters, Ulrike A1 - Preuss, Michael H A1 - Rao, D C A1 - Regan, Elizabeth A A1 - Reupena, Sefuiva M A1 - Roden, Dan M A1 - Rodriguez-Santana, Jose A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Tiwari, Hemant K A1 - Vasan, Ramachandran S A1 - Wang, Zeyuan A1 - Weeks, Daniel E A1 - Wessel, Jennifer A1 - Wiggins, Kerri L A1 - Wilkens, Lynne R A1 - Wilson, Peter W F A1 - Yanek, Lisa R A1 - Yoneda, Zachary T A1 - Zhao, Wei A1 - Zöllner, Sebastian A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Burchard, Esteban G A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Gordeuk, Victor R A1 - He, Jiang A1 - Heckbert, Susan R A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Kooperberg, Charles A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Nouraie, Mehdi A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Weiss, Scott T A1 - Zhang, Yingze A1 - Costa, Nancy Heard- A1 - Sun, Yan V A1 - Lin, Xihong A1 - Cupples, L Adrienne A1 - Lange, Leslie A A1 - Liu, Ching-Ti A1 - Loos, Ruth J F A1 - North, Kari E A1 - Justice, Anne E AB -

Obesity 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.

ER - TY - JOUR T1 - Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium. JF - bioRxiv Y1 - 2023 A1 - Jiang, Min-Zhi A1 - Gaynor, Sheila M A1 - Li, Xihao A1 - Van Buren, Eric A1 - Stilp, Adrienne A1 - Buth, Erin A1 - Wang, Fei Fei A1 - Manansala, Regina A1 - Gogarten, Stephanie M A1 - Li, Zilin A1 - Polfus, Linda M A1 - Salimi, Shabnam A1 - Bis, Joshua C A1 - Pankratz, Nathan A1 - Yanek, Lisa R A1 - Durda, Peter A1 - Tracy, Russell P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Mitchell, Braxton D A1 - Lewis, Joshua P A1 - Psaty, Bruce M A1 - Pratte, Katherine A A1 - Silverman, Edwin K A1 - Kaplan, Robert C A1 - Avery, Christy A1 - North, Kari A1 - Mathias, Rasika A A1 - Faraday, Nauder A1 - Lin, Honghuang A1 - Wang, Biqi A1 - Carson, April P A1 - Norwood, Arnita F A1 - Gibbs, Richard A A1 - Kooperberg, Charles A1 - Lundin, Jessica A1 - Peters, Ulrike A1 - Dupuis, Josée A1 - Hou, Lifang A1 - Fornage, Myriam A1 - Benjamin, Emelia J A1 - Reiner, Alexander P A1 - Bowler, Russell P A1 - Lin, Xihong A1 - Auer, Paul L A1 - Raffield, Laura M AB -

Inflammation 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.

ER - TY - JOUR T1 - Association analysis of mitochondrial DNA heteroplasmic variants: methods and application. JF - medRxiv Y1 - 2024 A1 - Sun, Xianbang A1 - Bulekova, Katia A1 - Yang, Jian A1 - Lai, Meng A1 - Pitsillides, Achilleas N A1 - Liu, Xue A1 - Zhang, Yuankai A1 - Guo, Xiuqing A1 - Yong, Qian A1 - Raffield, Laura M A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Abecasis, Goncalo A1 - Carson, April P A1 - Vasan, Ramachandran S A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fitzpatrick, Annette L A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Ding, Jun A1 - Levy, Daniel A1 - Liu, Chunyu AB -

We 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.

ER - TY - JOUR T1 - Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol. JF - JAMA Cardiol Y1 - 2024 A1 - Zhang, Yiyi A1 - Dron, Jacqueline S A1 - Bellows, Brandon K A1 - Khera, Amit V A1 - Liu, Junxiu A1 - Balte, Pallavi P A1 - Oelsner, Elizabeth C A1 - Amr, Sami Samir A1 - Lebo, Matthew S A1 - Nagy, Anna A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Rotter, Jerome I A1 - Willer, Cristen A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Lutsey, Pamela L A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Floyd, James S A1 - Vasan, Ramachandran S A1 - Heard-Costa, Nancy L A1 - Carson, April P A1 - Hall, Michael E A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Kazi, Dhruv S A1 - de Ferranti, Sarah D A1 - Moran, Andrew E AB -

IMPORTANCE: 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.

ER - TY - JOUR T1 - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. JF - Nature Y1 - 2024 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Melloni, Giorgio E M A1 - Kanoni, Stavroula A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Arruda, Ana Luiza A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Broadaway, K Alaine A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Thangam, Manonanthini A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Gordon-Larsen, Penny A1 - Gross, Myron A1 - Guare, Lindsay A A1 - Hackinger, Sophie A1 - Hakaste, Liisa A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Horikoshi, Momoko A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kamanu, Frederick K A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Moura, Filipe A A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Ahlqvist, Emma A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Marston, Nicholas A A1 - Ruff, Christian T A1 - van Heel, David A A1 - Finer, Sarah A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 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.

ER - TY - JOUR T1 - Human whole-exome genotype data for Alzheimer's disease. JF - Nat Commun Y1 - 2024 A1 - Leung, Yuk Yee A1 - Naj, Adam C A1 - Chou, Yi-Fan A1 - Valladares, Otto A1 - Schmidt, Michael A1 - Hamilton-Nelson, Kara A1 - Wheeler, Nicholas A1 - Lin, Honghuang A1 - Gangadharan, Prabhakaran A1 - Qu, Liming A1 - Clark, Kaylyn A1 - Kuzma, Amanda B A1 - Lee, Wan-Ping A1 - Cantwell, Laura A1 - Nicaretta, Heather A1 - Haines, Jonathan A1 - Farrer, Lindsay A1 - Seshadri, Sudha A1 - Brkanac, Zoran A1 - Cruchaga, Carlos A1 - Pericak-Vance, Margaret A1 - Mayeux, Richard P A1 - Bush, William S A1 - DeStefano, Anita A1 - Martin, Eden A1 - Schellenberg, Gerard D A1 - Wang, Li-San KW - Alzheimer Disease KW - Computational Biology KW - Data Accuracy KW - Exome KW - Genotype KW - Humans AB -

The 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.

VL - 15 IS - 1 ER - TY - JOUR T1 - Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. JF - Alzheimers Res Ther Y1 - 2024 A1 - Mei, Hao A1 - Simino, Jeannette A1 - Li, Lianna A1 - Jiang, Fan A1 - Bis, Joshua C A1 - Davies, Gail A1 - Hill, W David A1 - Xia, Charley A1 - Gudnason, Vilmundur A1 - Yang, Qiong A1 - Lahti, Jari A1 - Smith, Jennifer A A1 - Kirin, Mirna A1 - De Jager, Philip A1 - Armstrong, Nicola J A1 - Ghanbari, Mohsen A1 - Kolcic, Ivana A1 - Moran, Christopher A1 - Teumer, Alexander A1 - Sargurupremraj, Murali A1 - Mahmud, Shamsed A1 - Fornage, Myriam A1 - Zhao, Wei A1 - Satizabal, Claudia L A1 - Polasek, Ozren A1 - Räikkönen, Katri A1 - Liewald, David C A1 - Homuth, Georg A1 - Callisaya, Michele A1 - Mather, Karen A A1 - Windham, B Gwen A1 - Zemunik, Tatijana A1 - Palotie, Aarno A1 - Pattie, Alison A1 - van der Auwera, Sandra A1 - Thalamuthu, Anbupalam A1 - Knopman, David S A1 - Rudan, Igor A1 - Starr, John M A1 - Wittfeld, Katharina A1 - Kochan, Nicole A A1 - Griswold, Michael E A1 - Vitart, Veronique A1 - Brodaty, Henry A1 - Gottesman, Rebecca A1 - Cox, Simon R A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Sachdev, Perminder S A1 - Srikanth, Velandai A1 - Hayward, Caroline A1 - Wilson, James F A1 - Eriksson, Johan G A1 - Kardia, Sharon L R A1 - Grabe, Hans J A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Bressler, Jan A1 - Debette, Stephanie A1 - Mosley, Thomas H KW - Aged KW - Cognition KW - Genome-Wide Association Study KW - Humans KW - Memory KW - MicroRNAs KW - Multiomics KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: 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.

VL - 16 IS - 1 ER - TY - JOUR T1 - {Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications JF - Nat Commun Y1 - 2024 A1 - Sterenborg, R. B. T. M. A1 - Steinbrenner, I. A1 - Li, Y. A1 - Bujnis, M. N. A1 - Naito, T. A1 - Marouli, E. A1 - Galesloot, T. E. A1 - Babajide, O. A1 - Andreasen, L. A1 - Astrup, A. A1 - svold, B. O. A1 - Bandinelli, S. A1 - Beekman, M. A1 - Beilby, J. P. A1 - Bork-Jensen, J. A1 - Boutin, T. A1 - Brody, J. A. A1 - Brown, S. J. A1 - Brumpton, B. A1 - Campbell, P. J. A1 - Cappola, A. R. A1 - Ceresini, G. A1 - Chaker, L. A1 - Chasman, D. I. A1 - Concas, M. P. A1 - Coutinho de Almeida, R. A1 - Cross, S. M. A1 - Cucca, F. A1 - Deary, I. J. A1 - Kjaergaard, A. D. A1 - Echouffo Tcheugui, J. B. A1 - Ellervik, C. A1 - Eriksson, J. G. A1 - Ferrucci, L. A1 - Freudenberg, J. A1 - Fuchsberger, C. A1 - Gieger, C. A1 - Giulianini, F. A1 - gele, M. A1 - Graham, S. E. A1 - Grarup, N. A1 - ä, I. A1 - Hansen, T. A1 - Harding, B. N. A1 - Harris, S. E. A1 - ø, S. A1 - Hayward, C. A1 - Hui, J. A1 - Ittermann, T. A1 - Jukema, J. W. A1 - Kajantie, E. A1 - Kanters, J. K. A1 - rhus, L. L. A1 - Kiemeney, L. A. L. M. A1 - Kloppenburg, M. A1 - hnel, B. A1 - Lahti, J. A1 - Langenberg, C. A1 - Lapauw, B. A1 - Leese, G. A1 - Li, S. A1 - Liewald, D. C. M. A1 - Linneberg, A. A1 - Lominchar, J. V. T. A1 - Luan, J. A1 - Martin, N. G. A1 - Matana, A. A1 - Meima, M. E. A1 - Meitinger, T. A1 - Meulenbelt, I. A1 - Mitchell, B. D. A1 - llehave, L. T. A1 - Mora, S. A1 - Naitza, S. A1 - Nauck, M. A1 - Netea-Maier, R. T. A1 - Noordam, R. A1 - Nursyifa, C. A1 - Okada, Y. A1 - Onano, S. A1 - Papadopoulou, A. A1 - Palmer, C. N. A. A1 - Pattaro, C. A1 - Pedersen, O. A1 - Peters, A. A1 - Pietzner, M. A1 - ek, O. A1 - Pramstaller, P. P. A1 - Psaty, B. M. A1 - Punda, A. A1 - Ray, D. A1 - Redmond, P. A1 - Richards, J. B. A1 - Ridker, P. M. A1 - Russ, T. C. A1 - Ryan, K. A. A1 - Olesen, M. S. A1 - Schultheiss, U. T. A1 - Selvin, E. A1 - Siddiqui, M. K. A1 - Sidore, C. A1 - Slagboom, P. E. A1 - rensen, T. I. A. A1 - Soto-Pedre, E. A1 - Spector, T. D. A1 - Spedicati, B. A1 - Srinivasan, S. A1 - Starr, J. M. A1 - Stott, D. J. A1 - Tanaka, T. A1 - Torlak, V. A1 - Trompet, S. A1 - Tuhkanen, J. A1 - Uitterlinden, A. G. A1 - van den Akker, E. B. A1 - van den Eynde, T. A1 - van der Klauw, M. M. A1 - van Heemst, D. A1 - Verroken, C. A1 - Visser, W. E. A1 - Vojinovic, D. A1 - lzke, H. A1 - Waldenberger, M. A1 - Walsh, J. P. A1 - Wareham, N. J. A1 - Weiss, S. A1 - Willer, C. J. A1 - Wilson, S. G. A1 - Wolffenbuttel, B. H. R. A1 - Wouters, H. J. C. M. A1 - Wright, M. J. A1 - Yang, Q. A1 - Zemunik, T. A1 - Zhou, W. A1 - Zhu, G. A1 - llner, S. A1 - Smit, J. W. A. A1 - Peeters, R. P. A1 - ttgen, A. A1 - Teumer, A. A1 - Medici, M. AB - T3, 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. VL - 15 ER - TY - JOUR T1 - A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure. JF - ESC Heart Fail Y1 - 2024 A1 - Alkis, Taryn A1 - Luo, Xi A1 - Wall, Katherine A1 - Brody, Jennifer A1 - Bartz, Traci A1 - Chang, Patricia P A1 - Norby, Faye L A1 - Hoogeveen, Ron C A1 - Morrison, Alanna C A1 - Ballantyne, Christie M A1 - Coresh, Josef A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Shah, Amil M A1 - Yu, Bing AB -

AIMS: 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.

ER - TY - JOUR T1 - Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies. JF - Circulation Y1 - 2024 A1 - Laguzzi, Federica A1 - Åkesson, Agneta A1 - Marklund, Matti A1 - Qian, Frank A1 - Gigante, Bruna A1 - Bartz, Traci M A1 - Bassett, Julie K A1 - Birukov, Anna A1 - Campos, Hannia A1 - Hirakawa, Yoichiro A1 - Imamura, Fumiaki A1 - Jäger, Susanne A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Senn, Mackenzie A1 - Tanaka, Toshiko A1 - Tintle, Nathan A1 - Virtanen, Jyrki K A1 - Yamagishi, Kazumasa A1 - Allison, Matthew A1 - Brouwer, Ingeborg A A1 - de Faire, Ulf A1 - Eiriksdottir, Gudny A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Geleijnse, Johanna M A1 - Hodge, Allison M A1 - Kimura, Hitomi A1 - Laakso, Markku A1 - Riserus, Ulf A1 - van Westing, Anniek C A1 - Bandinelli, Stefania A1 - Baylin, Ana A1 - Giles, Graham G A1 - Gudnason, Vilmundur A1 - Iso, Hiroyasu A1 - Lemaitre, Rozenn N A1 - Ninomiya, Toshiharu A1 - Post, Wendy S A1 - Psaty, Bruce M A1 - Salonen, Jukka T A1 - Schulze, Matthias B A1 - Tsai, Michael Y A1 - Uusitupa, Matti A1 - Wareham, Nicholas J A1 - Oh, Seung-Won A1 - Wood, Alexis C A1 - Harris, William S A1 - Siscovick, David A1 - Mozaffarian, Dariush A1 - Leander, Karin KW - Animals KW - Biomarkers KW - Cardiovascular Diseases KW - Docosahexaenoic Acids KW - Fatty Acids, Omega-3 KW - Risk Factors AB -

BACKGROUND: 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.

VL - 149 IS - 4 ER - TY - JOUR T1 - X-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. JF - Nat Commun Y1 - 2024 A1 - Scholz, Markus A1 - Horn, Katrin A1 - Pott, Janne A1 - Wuttke, Matthias A1 - Kühnapfel, Andreas A1 - Nasr, M Kamal A1 - Kirsten, Holger A1 - Li, Yong A1 - Hoppmann, Anselm A1 - Gorski, Mathias A1 - Ghasemi, Sahar A1 - Li, Man A1 - Tin, Adrienne A1 - Chai, Jin-Fang A1 - Cocca, Massimiliano A1 - Wang, Judy A1 - Nutile, Teresa A1 - Akiyama, Masato A1 - Åsvold, Bjørn Olav A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boutin, Thibaud A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Burkhardt, Ralph A1 - Cai, Jianwen A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chalmers, John A1 - Chasman, Daniel I A1 - Chee, Miao Ling A1 - Chee, Miao Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cifkova, Renata A1 - Daviglus, Martha A1 - Delgado, Graciela A1 - Dittrich, Katalin A1 - Edwards, Todd L A1 - Endlich, Karlhans A1 - Michael Gaziano, J A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Heid, Iris M A1 - Hellwege, Jacklyn N A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Isermann, Berend A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Khor, Chiea Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuokkanen, Mikko A1 - Kähönen, Mika A1 - Lange, Leslie A A1 - Lash, James P A1 - Lehtimäki, Terho A1 - Li, Hengtong A1 - Lin, Bridget M A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Matsuda, Koichi A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - März, Winfried A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - Okada, Yukinori A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Pirastu, Nicola A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poulain, Tanja A1 - Psaty, Bruce M A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rasheed, Humaira A1 - Reilly, Dermot F A1 - Rice, Kenneth M A1 - Richmond, Anne A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Schneiderman, Neil A1 - Schöttker, Ben A1 - Sims, Mario A1 - Snieder, Harold A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Stocker, Hannah A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Svensson, Per O A1 - Tai, E-Shyong A1 - Taylor, Kent D A1 - Tayo, Bamidele O A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomas, Laurent F A1 - Tremblay, Johanne A1 - Tönjes, Anke A1 - van der Most, Peter J A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Wei, Wen Bin A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Winkler, Thomas W A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Sim, Xueling A1 - Chu, Audrey Y A1 - Feitosa, Mary F A1 - Thorsteinsdottir, Unnur A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Franceschini, Nora A1 - Parsa, Afshin A1 - Köttgen, Anna A1 - Schlosser, Pascal A1 - Pattaro, Cristian KW - Androgens KW - Chromosomes, Human, X KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Polymorphism, Single Nucleotide KW - Response Elements KW - Tetraspanins AB -

X-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.

VL - 15 IS - 1 ER -