02473nas a2200373 4500008004100000022001400041245009600055210006900151260001600220300001100236490000800247520142800255653003101683653000901714653002201723653001801745653002401763653001401787653002801801653001501829653001101844653002501855653001101880653001801891653003101909653000901940653003701949653001701986653001802003100001202021700001602033700001502049856003502064 1999 eng d a0002-926200aNeuroanatomic and functional correlates of depressed mood: the Cardiovascular Health Study.0 aNeuroanatomic and functional correlates of depressed mood the Ca c1999 Nov 01 a919-290 v1503 a
Although a number of studies suggest an association between stroke and depression, few have examined the relation between magnetic resonance imaging (MRI)-identified lesions and depression among community-dwelling older adults. This cross-sectional study sought to assess the association between MRI infarcts in the basal ganglia and non-basal-ganglia areas, potential functional consequences of these lesions, and depressive symptomatology in 3,371 US men and women aged 65 years or older who participated in the Cardiovascular Health Study between 1992 and 1994. By using multiple linear regression models, the authors found that after adjustment for age, gender, and stroke history, Center for Epidemiologic Studies Depression Scale scores were independently associated with non-basal-ganglia lesions (p = 0.04) but were not independently associated with basal ganglia lesions (p = 0.11). When measures of physical disability and cognitive impairment were added to the models, these measures displaced MRI-identified infarcts in their association with depressive symptoms. In additional models, hemispheric location and size of the basal ganglia lesion were found to have no relation to depression levels. These results suggest that the functional consequences of cerebrovascular disease may be the causal pathway by which basal ganglia and non-basal-ganglia lesions are associated with depressive symptomatology.
10aActivities of Daily Living10aAged10aAged, 80 and over10aBasal Ganglia10aCerebral Infarction10aCognition10aCross-Sectional Studies10aDepression10aFemale10aGeriatric Assessment10aHumans10aLinear Models10aMagnetic Resonance Imaging10aMale10aPsychiatric Status Rating Scales10aRisk Factors10aUnited States1 aSato, R1 aBryan, R, N1 aFried, L P uhttps://chs-nhlbi.org/node/60401932nas a2200349 4500008004100000022001400041245013700055210006900192260001300261300001100274490000700285520098400292653000901276653001201285653001501297653001501312653002101327653001101348653002001359653001801379653001101397653002501408653000901433653001801442653001601460653001201476100001601488700001401504700001401518700001501532856003501547 2000 eng d a0882-797400aNegative and positive health effects of caring for a disabled spouse: longitudinal findings from the caregiver health effects study.0 aNegative and positive health effects of caring for a disabled sp c2000 Jun a259-710 v153 aData from the first 2 waves of the Caregiver Health Effects Study (n = 680) were analyzed to examine the effects of changes in caregiving involvement on changes in caregiver health-related outcomes in a population-based sample of elders caring for a disabled spouse. Caregiving involvement was indexed by levels of (a) spouse physical impairment, (b) help provided to the spouse, and (c) strain associated with providing help. Health-related outcomes included perceived health, health-risk behaviors, anxiety symptoms, and depression symptoms. Increases in spouse impairment and caregiver strain were generally related to poorer outcomes over time (poorer perceived health, increased health-risk behaviors, and increased anxiety and depression), whereas increased helping was related to better outcomes (decreased anxiety and depression). Results suggest that caring for a disabled spouse is a complex phenomenon that can have both deleterious and beneficial consequences.
10aAged10aAnxiety10aCaregivers10aDepression10aDisabled Persons10aFemale10aHealth Behavior10aHealth Status10aHumans10aLongitudinal Studies10aMale10aMental Health10aRisk-Taking10aSpouses1 aBeach, S, R1 aSchulz, R1 aYee, J, L1 aJackson, S uhttps://chs-nhlbi.org/node/61902831nas a2200361 4500008004100000245012600041210006900167260001500236300000800251490000600259520186400265653001002129653001002139653002002149653001202169653001102181653001202192653001502204653003102219653001202250653001502262653001502277653001502292653001102307100001902318700001602337700001402353700001602367700001902383700001502402700001602417856003602433 2000 eng d00aNeurologic correlates of infarction-like lesion location on magnetic resonance imaging in the cardiovascular health study0 aNeurologic correlates of infarctionlike lesion location on magne c2000-01-01 a2280 v93 aObjective: To evaluate and quantify the associations of infarction-like lesion location in the brain with cognitive and physical impairment in an elderly population. Methods: Data from magnetic resonance imaging (MRI) scans for 3647 Cardiovascular Health Study participants were analyzed. Associations between infarction-like lesion location and various neurologic and performance-based measurements were assessed by using regression models. Continuous responses were expressed in percentiles. Models excluding participants with a history of stroke were also examined. Results: Brainstem infarction-like lesions were associated with a severely reduced Mini-Mental State Examination score (difference [d] = 15 percentiles, P < .001), reduced digit-symbol score (d = 12 percentiles, P < .01), increased time to walk 15 feet (d = 15 percentiles, P < .001), and increased odds of a history of dizziness (odds ratio [OR] = 2.5, P <.01). Basal ganglia infarctions were associated with an increased prevalence of visual field deficits (OR = 1.8, P <.001), and cerebellar white matter infarction-like lesions with an increased prevalence of a history of coma (OR = 4.0, P < .01). For those with infarction-like lesions in both the cerebral cortex and brainstem, the degree of sleepiness was substantially elevated (d = 34 percentiles, P < .01). No associations with a history of migraines were detected. After exclusion of those with stroke history, all of these associations persisted. Conclusion: The estimated magnitude and statistical significance of these associations relative to those with no infarction-like lesions provides new information. Further investigation for some of the associations, such as the role of the brainstem in cognitive function and the association of basal ganglia infarction-like lesions with visual field deficits, would be worthwhile.10abasal10aBrain10aCerebral Cortex10aganglia10aHealth10ahistory10aInfarction10aMagnetic Resonance Imaging10amethods10aOdds Ratio10aPopulation10aPrevalence10aStroke1 aMcClelland, RL1 aKronmal, RA1 aBryan, RN1 aManolio, TA1 aHerskovits, EH1 aKuller, LH1 aO'Leary, DH uhttps://chs-nhlbi.org/node/152801497nas a2200325 4500008004100000022001400041245008500055210006900140260001300209300001100222490000700233520062700240653000900867653002200876653002200898653001100920653001100931653000900942653002900951653002800980653002101008100001401029700001601043700001601059700001701075700001701092700001301109700001401122856003501136 2000 eng d a1385-404600aNormative data on the Boston Naming Test and two equivalent 30-item short forms.0 aNormative data on the Boston Naming Test and two equivalent 30it c2000 Nov a526-340 v143 aBecause of the significance of the Boston Naming Test (BNT) in the differential diagnosis of the dementias, especially Alzheimer's disease, adequate norms from community-dwelling elderly individuals are essential. The present study describes the development of two new empirically derived equivalent short forms (30 items each) of the test. Normative data for the total BNT and the two equivalent 30-item halves based on item difficulty are presented using the performance of 314 community-dwelling individuals aged 65 and over. Age and education norms are presented using an overlapping midpoint interval strategy.
10aAged10aAged, 80 and over10aAlzheimer Disease10aFemale10aHumans10aMale10aNeuropsychological Tests10aPopulation Surveillance10aReference Values1 aSaxton, J1 aRatcliff, G1 aMunro, C, A1 aCoffey, E, C1 aBecker, J, T1 aFried, L1 aKuller, L uhttps://chs-nhlbi.org/node/64102711nas a2200505 4500008004100000022001400041245016300055210006900218260001300287300001100300490000700311520127900318653002801597653000901625653002201634653001201656653002001668653001901688653002801707653002501735653001601760653002201776653001101798653003801809653001101847653002001858653001701878653000901895653001301904653002601917653001201943653003001955653001601985653001702001653001202018653001102030653001202041100002002053700002002073700001902093700001802112700001802130700002202148856003502170 2002 eng d a0340-624500aNo association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study.0 aNo association of plasma prothrombin concentration or the G20210 c2002 Apr a614-210 v873 aProthrombin is a key factor in blood clotting, a process intimately involved in thrombotic disease. We assessed prothrombin levels and G20210A genotype in a case-control study within the Cardiovascular Health Study. Cases included angina, myocardial infarction, stroke, and the presence of MRI-detectable infarcts (n approximately 250 each). Population-based controls free of clinical cardiovascular disease (CVD) (n approximately 500) and a subset free of clinical and subclinical CVD (n approximately 250) were used for comparison. The 20210 A allele, frequency 2.9%, was associated with higher mean prothrombin levels: 166.3 vs. 139.5 microg/ml (P <0.001). Significant correlates of prothrombin included gender, plasma lipids, other vitamin K-dependent proteins, and inflammatory markers, but not race, smoking, hypertension, diabetes, measures of subclinical CVD, or markers of procoagulant activity. Compared to controls, neither genotype nor prothrombin level was associated with any CVD case group. We conclude that, in the elderly, neither prothrombin level nor 20210 genotype were associated with either CVD risk factors or events. This is consistent with the lack of association of prothrombin levels with measures of underlying CVD or procoagulant markers.
10a3' Untranslated Regions10aAged10aAged, 80 and over10aAlleles10aAngina Pectoris10aBlood Proteins10aCardiovascular Diseases10aCase-Control Studies10aComorbidity10aDiabetes Mellitus10aFemale10aGenetic Predisposition to Disease10aHumans10aHyperlipidemias10aHypertension10aMale10aMutation10aMyocardial Infarction10aObesity10aPromoter Regions, Genetic10aProthrombin10aRisk Factors10aSmoking10aStroke10aVermont1 aSmiles, Adam, M1 aJenny, Nancy, S1 aTang, Zhonghua1 aArnold, Alice1 aCushman, Mary1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/69003032nas a2200445 4500008004100000022001400041245013100055210006900186260001600255300001200271490000700283520175100290653000902041653001002050653002602060653002502086653001902111653002102130653001102151653001802162653001102180653002202191653002202213653002302235653003602258653000902294653004502303653001702348653001602365100001802381700001802399700001902417700001702436700001602453700001702469700002102486700002302507700002102530856003502551 2002 eng d a1524-463600aNuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study.0 aNuclear magnetic resonance spectroscopy of lipoproteins and risk c2002 Jul 01 a1175-800 v223 aOBJECTIVES: Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis.
METHODS AND RESULTS: The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 "healthy" participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between "healthy" participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina.
CONCLUSIONS: Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.
10aAged10aAging10aCardiovascular System10aCase-Control Studies10aCohort Studies10aCoronary Disease10aFemale10aHealth Status10aHumans10aLipoproteins, HDL10aLipoproteins, LDL10aLipoproteins, VLDL10aMagnetic Resonance Spectroscopy10aMale10aNuclear Magnetic Resonance, Biomolecular10aRisk Factors10aSex Factors1 aKuller, Lewis1 aArnold, Alice1 aTracy, Russell1 aOtvos, James1 aBurke, Greg1 aPsaty, Bruce1 aSiscovick, David1 aFreedman, David, S1 aKronmal, Richard uhttps://chs-nhlbi.org/node/69603213nas a2200457 4500008004100000022001400041245015200055210006900207260001300276300001100289490000700300520188900307653000902196653002502205653001502230653002502245653001902270653002102289653002402310653002602334653002602360653002502386653001102411653001402422653001102436653001402447653000902461653002602470653001502496653001802511653001502529653002402544653001702568100002402585700001902609700002502628700002102653700002202674700002402696856003502720 2003 eng d a0002-916500an-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study.0 an3 Polyunsaturated fatty acids fatal ischemic heart disease and c2003 Feb a319-250 v773 aBACKGROUND: Little is known about the relation of the dietary intake of n-3 polyunsaturated fatty acids, ie, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fatty fish and alpha-linolenic acid from vegetable oils, with ischemic heart disease among older adults.
OBJECTIVE: We investigated the associations of plasma phospholipid concentrations of DHA, EPA, and alpha-linolenic acid as biomarkers of intake with the risk of incident fatal ischemic heart disease and incident nonfatal myocardial infarction in older adults.
DESIGN: We conducted a case-control study nested in the Cardiovascular Health Study, a cohort study of adults aged > or = 65 y. Cases experienced incident fatal myocardial infarction and other ischemic heart disease death (n = 54) and incident nonfatal myocardial infarction (n = 125). Matched controls were randomly selected (n = 179). We measured plasma phospholipid concentrations of n-3 polyunsaturated fatty acids in blood samples drawn approximately 2 y before the event.
RESULTS: A higher concentration of combined DHA and EPA was associated with a lower risk of fatal ischemic heart disease, and a higher concentration of alpha-linolenic acid with a tendency to lower risk, after adjustment for risk factors [odds ratio: 0.32 (95% CI: 0.13, 0.78; P = 0.01) and 0.52 (0.24, 1.15; P = 0.1), respectively]. In contrast, n-3 polyunsaturated fatty acids were not associated with nonfatal myocardial infarction.
CONCLUSIONS: Higher combined dietary intake of DHA and EPA, and possibly alpha-linolenic acid, may lower the risk of fatal ischemic heart disease in older adults. The association of n-3 polyunsaturated fatty acids with fatal ischemic heart disease, but not with nonfatal myocardial infarction, is consistent with possible antiarrhythmic effects of these fatty acids.
10aAged10aalpha-Linolenic Acid10aBiomarkers10aCase-Control Studies10aCohort Studies10aCoronary Disease10aDietary Supplements10aDocosahexaenoic Acids10aEicosapentaenoic Acid10aFatty Acids, Omega-310aFemale10aFish Oils10aHumans10aIncidence10aMale10aMyocardial Infarction10aOdds Ratio10aPhospholipids10aPrevalence10aProspective Studies10aRisk Factors1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aMozaffarian, Dariush1 aKuller, Lewis, H1 aTracy, Russell, P1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/72203027nas a2200361 4500008004100000022001400041245011300055210006900168260001300237300001100250490000700261520198700268653002202255653000902277653002802286653004002314653001102354653002202365653001102387653001102398653000902409653001802418653003002436653001702466653002602483653001802509100002202527700002202549700001502571700002302586700002102609856003502630 2004 eng d a0143-005X00aNeighbourhood environments and mortality in an elderly cohort: results from the cardiovascular health study.0 aNeighbourhood environments and mortality in an elderly cohort re c2004 Nov a917-230 v583 aBACKGROUND: It has been postulated that neighbourhood conditions are related to the health of the elderly population but longitudinal studies are rare and confounding by individual level variables remains a possibility.
METHODS: Data were obtained from the cardiovascular health study, a population based study of adults aged 65 years and older. Census block groups were used as proxies for neighbourhoods. A summary score was used to characterise the neighbourhood socioeconomic environment. Information on personal socioeconomic indicators, cardiovascular disease prevalence, and cardiovascular risk factors was obtained from the baseline examination. Proportional hazards regression and propensity score matching were used to control for individual level variables.
RESULTS: Over the eight year follow up there were 1346 deaths among the 5074 participants, of which 43% were attributable to cardiovascular disease. Among white participants, living in the most disadvantaged neighbourhood group was associated with higher rates of cardiovascular death, after adjustment for income, education, and occupation (hazard ratio (HR) 1.5, 95% confidence intervals (CI) 1.2 to 1.9). No neighbourhood differences were observed for non-cardiovascular deaths. Estimates for black participants were 1.3 (95% CI 0.7 to 2.3) for cardiovascular deaths and 1.4 (95% CI 0.8 to 2.4) for non-cardiovascular deaths, but sample size was small. In white participants, associations of neighbourhood characteristics with cardiovascular mortality persisted after adjustment for prevalent baseline disease and cardiovascular risk factors. The use of propensity score matching led to similar results (HR for the lowest compared with the highest neighbourhood score group: 1.6 95% CI 1.1 to 2.5, controlling for personal socioeconomic indicators).
CONCLUSION: Neighbourhood disadvantage is related to rates of cardiovascular death in elderly white adults.
10aAfrican Americans10aAged10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHumans10aIncome10aMale10aPoverty Areas10aResidence Characteristics10aRisk Factors10aSocioeconomic Factors10aUnited States1 aRoux, Ana, V Diez1 aBorrell, Luisa, N1 aHaan, Mary1 aJackson, Sharon, A1 aSchultz, Richard uhttps://chs-nhlbi.org/node/80902803nas a2200397 4500008004100000022001400041245007900055210006900134260001300203300001100216490000700227520176600234653000902000653002202009653002202031653001202053653002402065653001102089653001102100653000902111653002902120653001802149653002102167100001602188700001702204700001702221700001902238700001802257700001802275700001602293700001902309700001302328700001302341700001602354856003502370 2006 eng d a0022-305000aNeuropsychological characteristics of mild cognitive impairment subgroups.0 aNeuropsychological characteristics of mild cognitive impairment c2006 Feb a159-650 v773 aOBJECTIVE: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study.
METHODS: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition.
RESULTS: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits.
CONCLUSIONS: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.
10aAged10aAged, 80 and over10aAlzheimer Disease10aAmnesia10aCognition Disorders10aFemale10aHumans10aMale10aNeuropsychological Tests10aPsychometrics10aReference Values1 aLopez, O, L1 aBecker, J, T1 aJagust, W, J1 aFitzpatrick, A1 aCarlson, M, C1 aDeKosky, S, T1 aBreitner, J1 aLyketsos, C, G1 aJones, B1 aKawas, C1 aKuller, L H uhttps://chs-nhlbi.org/node/85102785nas a2200361 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520173700263653000902000653002202009653002002031653001802051653002802069653002702097653002202124653002202146653001102168653002602179653001702205653001802222653001702240100002302257700002402280700002102304700001902325700002402344700002002368856003502388 2006 eng d a0149-599200aNew-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study.0 aNewonset diabetes and risk of allcause and cardiovascular mortal c2006 Sep a2012-70 v293 aOBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes.
RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality.
RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time.
CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.
10aAged10aAged, 80 and over10aAtherosclerosis10aBlood Glucose10aCardiovascular Diseases10aDiabetes Complications10aDiabetes Mellitus10aFollow-Up Studies10aHumans10aKaplan-Meier Estimate10aRisk Factors10aSurvival Rate10aTime Factors1 aSmith, Nicholas, L1 aBarzilay, Joshua, I1 aKronmal, Richard1 aLumley, Thomas1 aEnquobahrie, Daniel1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/91401635nas a2200205 4500008004100000245004400041210003900085260001500124490000700139520111200146653001001258653001601268653002901284653002601313100001301339700001501352700001501367700001101382856003601393 2007 eng d00aThe number of sick persons in a cohort.0 anumber of sick persons in a cohort c2007-01-010 v293 aIn the Cardiovascular Health Study, a cohort study of older adults followed up to 14 years, the number of sick persons was approximately constant over time. This was true whether we defined “sick” based on self-rated health, ADL or IADL difficulties, the timed walk, bed days, depression, cognitive problems, or cardiovascular disease. To better understand this phenomenon, we estimated the probabilities of transition among the healthy, sick, and dead states, and projected the number who would be in each health state over time for a birth cohort. The estimated number of sick persons in the birth cohort increased slowly over time and was approximately constant from ages 55-75, after which it decreased. The relative excess of older persons who are sick in later life is caused by a decline in the number of healthy persons rather than an increase in the number who are sick. Estimated total medical expenditures for a birth cohort may decline after about age 73. These findings may suggest a different way of thinking about trends in the health and medical expenditures of the population over time.10aAging10aequilibrium10atransition probabilities10ayears of healthy life1 aDiehr, P1 aDerleth, A1 aNewman, AB1 aCai, L uhttps://chs-nhlbi.org/node/153103257nas a2200565 4500008004100000022001400041245011300055210006900168260001600237300001100253490000700264520171200271653001801983653001502001653001002016653000902026653002202035653002202057653002602079653002902105653004402134653001202178653001902190653001102209653001102220653000902231653001602240653002702256653002202283653003202305653002402337653001702361100001802378700001602396700002102412700001702433700001702450700001802467700001602485700001502501700001602516700001602532700001502548700001802563700001502581700002002596700002302616700001602639856003602655 2008 eng d a1526-632X00aNo advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.0 aNo advantage of A beta 42lowering NSAIDs for prevention of Alzhe c2008 Jun 10 a2291-80 v703 aINTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.
METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.
RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13).
CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.
10aAcetaminophen10aAdolescent10aAdult10aAged10aAged, 80 and over10aAlzheimer Disease10aAmyloid beta-Peptides10aAnalgesics, Non-Narcotic10aAnti-Inflammatory Agents, Non-Steroidal10aAspirin10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aNeuroprotective Agents10aPeptide Fragments10aProportional Hazards Models10aProspective Studies10aRisk Factors1 aSzekely, C, A1 aGreen, R, C1 aBreitner, J, C S1 astbye, T, Ø1 aBeiser, A, S1 aCorrada, M, M1 aDodge, H, H1 aGanguli, M1 aKawas, C, H1 aKuller, L H1 aPsaty, B M1 aResnick, S, M1 aWolf, P, A1 aZonderman, A, B1 aWelsh-Bohmer, K, A1 aZandi, P, P uhttps://chs-nhlbi.org/node/103403075nas a2200421 4500008004100000022001400041245018900055210006900244260001300313300001200326490000700338520176300345653000902108653002202117653002502139653002702164653003602191653001102227653001502238653001102253653000902264653001302273653003102286653002002317653001702337653003202354653002202386653001802408100002202426700002402448700002302472700002802495700002602523700002402549700002102573700002302594856003602617 2008 eng d a1540-816700aNovel measures of heart rate variability predict cardiovascular mortality in older adults independent of traditional cardiovascular risk factors: the Cardiovascular Health Study (CHS).0 aNovel measures of heart rate variability predict cardiovascular c2008 Nov a1169-740 v193 aUNLABELLED: Novel HRV Predicts CV Mortality in the Elderly.
BACKGROUND: It is unknown whether abnormal heart rate turbulence (HRT) and abnormal fractal properties of heart rate variability identify older adults at increased risk of cardiovascular death (CVdth).
METHODS: Data from 1,172 community-dwelling adults, ages 72 +/- 5 (65-93) years, who participated in the Cardiovascular Health Study (CHS), a study of risk factors for CV disease in people >or=65 years. HRT and the short-term fractal scaling exponent (DFA1) derived from 24-hour Holter recordings. HRT categorized as: normal (turbulence slope [TS] and turbulence onset [TO] normal) or abnormal (TS and/or TO abnormal). DFA1 categorized as low (
RESULTS: CVdths (N = 172) occurred over a median follow-up of 12.3 years. Within each FRS stratum, low DFA1 + abnormal HRT predicted risk of CVdth (RR = 7.7 for low FRS; 3.6, mid FRS; 2.8, high FRS). Among high FRS stratum participants, low DFA1 alone also predicted CVdth (RR = 2.0). VPCs in the highest quartile predicted CVdth, but only in the high FRS group. Clinical CV disease predicted CVdth at each FRS stratum (RR = 2.9, low; 2.6, mid; and 1.9, high). Diabetes predicted CVdth in the highest FRS group only (RR = 2.2).
CONCLUSIONS: The combination of low DFA1 + abnormal HRT is a strong risk factor for CVdth among older adults even after adjustment for conventional CVD risk measures and the presence of CVD.
10aAged10aAged, 80 and over10aArrhythmias, Cardiac10aDeath, Sudden, Cardiac10aElectrocardiography, Ambulatory10aFemale10aHeart Rate10aHumans10aMale10aMaryland10aReproducibility of Results10aRisk Assessment10aRisk Factors10aSensitivity and Specificity10aSurvival Analysis10aSurvival Rate1 aStein, Phyllis, K1 aBarzilay, Joshua, I1 aChaves, Paulo, H M1 aMistretta, Stephanie, Q1 aDomitrovich, Peter, P1 aGottdiener, John, S1 aRich, Michael, W1 aKleiger, Robert, E uhttps://chs-nhlbi.org/node/104202815nas a2200385 4500008004100000022001400041245009700055210006900152260001600221300001000237490000700247520174200254653000901996653002202005653002202027653004402049653002202093653002602115653001302141653001102154653001102165653001402176653000902190653003202199653002402231653001702255100001802272700002102290700002202311700001402333700001502347700001602362700001602378856003502394 2008 eng d a1526-632X00aNSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.0 aNSAID use and dementia risk in the Cardiovascular Health Study r c2008 Jan 01 a17-240 v703 aBACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.
METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant A beta(42).
RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42).
CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.
10aAged10aAged, 80 and over10aAlzheimer Disease10aAnti-Inflammatory Agents, Non-Steroidal10aApolipoproteins E10aCardiovascular System10aDementia10aFemale10aHumans10aIncidence10aMale10aProportional Hazards Models10aProspective Studies10aRisk Factors1 aSzekely, C, A1 aBreitner, J, C S1 aFitzpatrick, A, L1 aRea, T, D1 aPsaty, B M1 aKuller, L H1 aZandi, P, P uhttps://chs-nhlbi.org/node/99804323nas a2201033 4500008004100000022001400041245011200055210006900167260001300236300001300249490000600262520134000268653000901608653002001617653001901637653004001656653001101696653003801707653003401745653001101779653000901790653001601799653002601815653001201841653003601853653002401889100002601913700002501939700001901964700001901983700002202002700001202024700002302036700002102059700001902080700002402099700002002123700002202143700002102165700002502186700002402211700002302235700002602258700002102284700001902305700002302324700002102347700002102368700002202389700002202411700002202433700002002455700002202475700001602497700002002513700002002533700002202553700002602575700001602601700002302617700002202640700001602662700001602678700002502694700001902719700002102738700001902759700002402778700002402802700003002826700002702856700002202883700002402905700001902929700001902948700002602967700002802993700003003021700001903051700002203070700002403092700002603116700002303142700002303165700002503188700002103213700001903234856003603253 2009 eng d a1553-740400aNRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.0 aNRXN3 is a novel locus for waist circumference a genomewide asso c2009 Jun ae10005390 v53 aCentral abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
10aAged10aBody Mass Index10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aObesity10aPolymorphism, Single Nucleotide10aWaist Circumference1 aHeard-Costa, Nancy, L1 aZillikens, Carola, M1 aMonda, Keri, L1 aJohansson, Asa1 aHarris, Tamara, B1 aFu, Mao1 aHaritunians, Talin1 aFeitosa, Mary, F1 aAspelund, Thor1 aEiriksdottir, Gudny1 aGarcia, Melissa1 aLauner, Lenore, J1 aSmith, Albert, V1 aMitchell, Braxton, D1 aMcArdle, Patrick, F1 aShuldiner, Alan, R1 aBielinski, Suzette, J1 aBoerwinkle, Eric1 aBrancati, Fred1 aDemerath, Ellen, W1 aPankow, James, S1 aArnold, Alice, M1 aChen, Yii-Der Ida1 aGlazer, Nicole, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aAmin, Najaf1 aCampbell, Harry1 aGyllensten, Ulf1 aPattaro, Cristian1 aPramstaller, Peter, P1 aRudan, Igor1 aStruchalin, Maksim1 aVitart, Veronique1 aGao, Xiaoyi1 aKraja, Aldi1 aProvince, Michael, A1 aZhang, Qunyuan1 aAtwood, Larry, D1 aDupuis, Josée1 aHirschhorn, Joel, N1 aJaquish, Cashell, E1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWhite, Charles, C1 aAulchenko, Yurii, S1 aEstrada, Karol1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aOostra, Ben, A1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aFox, Caroline, S1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/110702964nas a2200385 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295520179300303653000902096653002202105653002402127653001102151653001102162653001602173653002502189653000902214653003102223653002202254653003002276653001502306653003202321653001702353100002302370700002402393700002302417700002702440700002702467700002402494700002402518856003602542 2009 eng d a1524-453900aN-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study.0 aNterminal proBtype natriuretic peptide is a major predictor of t c2009 Nov 03 a1768-740 v1203 aBACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality.
METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95% confidence interval, 3.2 to 5.0; P<0.001).
CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
10aAged10aAged, 80 and over10aAtrial Fibrillation10aFemale10aHumans10aImmunoassay10aLongitudinal Studies10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aPrevalence10aProportional Hazards Models10aRisk Factors1 aPatton, Kristen, K1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aChristenson, Robert, H1 aDeFilippi, Christopher1 aGottdiener, John, S1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/113812636nas a2204069 4500008004100000022001400041245010500055210006900160260001300229300001100242490000700253520123400260653001501494653001001509653001201519653001801531653001001549653002301559653003001582653003101612653001201643653003101655653001701686653003801703653003401741653001601775653001101791653002701802653003601829653002801865653003401893653003101927100001901958700002401977700002102001700001802022700002002040700002102060700002102081700002202102700002502124700001902149700002502168700001802193700002202211700002002233700001802253700001802271700001702289700002502306700003202331700002002363700002102383700001902404700002402423700002902447700001702476700001802493700001502511700002102526700002302547700001902570700001802589700002002607700001602627700002402643700002602667700001202693700002202705700001902727700003502746700001802781700001102799700002502810700002202835700001902857700002402876700002002900700001302920700002302933700001802956700002002974700002502994700002003019700002703039700002203066700002403088700002003112700002003132700002103152700001903173700002003192700002103212700002303233700002303256700001903279700002103298700002103319700002303340700002503363700002403388700002203412700001803434700002703452700002703479700002203506700001803528700001903546700002303565700002303588700002203611700001903633700002003652700001803672700001903690700002303709700002003732700002203752700002303774700002803797700002103825700002103846700001703867700002703884700001703911700002203928700002303950700002703973700001804000700002004018700002004038700001804058700002104076700001904097700001604116700002804132700002204160700002204182700002004204700002004224700002204244700002104266700002204287700002404309700001904333700001604352700001404368700001504382700002304397700002304420700001604443700002104459700001904480700002504499700001904524700002104543700002004564700001804584700002304602700002104625700002204646700002404668700002104692700001204713700002304725700001904748700002104767700002204788700003604810700002304846700002404869700002004893700002304913700001804936700001704954700002504971700002104996700002205017700001905039700001905058700002405077700001905101700001705120700001605137700002305153700002305176700002205199700002005221700001905241700002305260700001905283700002705302700001905329700001905348700002305367700002105390700001805411700002505429700002005454700002305474700002105497700001805518700002005536700002605556700001905582700002105601700002205622700002205644700001805666700002205684700001705706700002005723700001705743700002205760700002205782700002505804700002505829700002105854700001905875700002205894700002305916700001605939700001505955700001905970700002805989700002006017700002106037700001706058700001806075700002206093700002806115700002106143700001606164700001806180700002706198700002206225700002306247700002006270700002106290700001906311700002206330700001706352700001806369700002306387700001906410700002306429700002906452700002306481700002406504700002006528700002206548700001806570700001906588700002506607700002306632700002006655700002006675700002706695700002106722700002406743700002606767700002006793700002006813700002406833700002506857700001906882700002206901700001906923700002306942700001806965700002506983700002607008700002207034700001507056700002007071700001707091700002007108700001807128700002007146700002007166700002107186700002407207700002207231700001907253700001907272700001907291700002807310700002307338700001807361700001607379700002007395700002207415700002007437700002107457700002407478700002407502700002407526700002107550700002307571700001907594700002107613700002207634700002407656700002707680700002307707700002007730700002407750700002507774700002007799700002007819700002807839700002107867700002307888700002407911700001707935700002007952700002407972700001707996700001908013700002708032700002408059700002408083700002008107700002008127700002508147700002508172700001908197700002208216700002508238700002008263700001608283700002108299700002208320700002008342700001908362710002308381710002108404710002808425710005308453710002408506856003608530 2010 eng d a1546-171800aNew genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.0 aNew genetic loci implicated in fasting glucose homeostasis and t c2010 Feb a105-160 v423 aLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
10aAdolescent10aAdult10aAlleles10aBlood Glucose10aChild10aDatabases, Genetic10aDiabetes Mellitus, Type 210aDNA Copy Number Variations10aFasting10aGene Expression Regulation10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeostasis10aHumans10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aReproducibility of Results1 aDupuis, Josée1 aLangenberg, Claudia1 aProkopenko, Inga1 aSaxena, Richa1 aSoranzo, Nicole1 aJackson, Anne, U1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aGloyn, Anna, L1 aLindgren, Cecilia, M1 aMägi, Reedik1 aMorris, Andrew, P1 aRandall, Joshua1 aJohnson, Toby1 aElliott, Paul1 aRybin, Denis1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aHenneman, Peter1 aGrallert, Harald1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aFranklin, Christopher, S1 aNavarro, Pau1 aSong, Kijoung1 aGoel, Anuj1 aPerry, John, R B1 aEgan, Josephine, M1 aLajunen, Taina1 aGrarup, Niels1 aSparsø, Thomas1 aDoney, Alex1 aVoight, Benjamin, F1 aStringham, Heather, M1 aLi, Man1 aKanoni, Stavroula1 aShrader, Peter1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aQi, Lu1 aTimpson, Nicholas, J1 aGieger, Christian1 aZabena, Carina1 aRocheleau, Ghislain1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aPayne, Felicity1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aArdlie, Kristin1 aAriyurek, Yavuz1 aBalkau, Beverley1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBonnefond, Amélie1 aBonnycastle, Lori, L1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aCharpentier, Guillaume1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCornelis, Marilyn1 aCrawford, Gabe1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aDina, Christian1 aErdos, Michael, R1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFox, Caroline, S1 aFrants, Rune1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGroves, Christopher, J1 aGrundy, Scott1 aGwilliam, Rhian1 aGyllensten, Ulf1 aHadjadj, Samy1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHerder, Christian1 aHicks, Andrew, A1 aHillman, David, R1 aHingorani, Aroon, D1 aHofman, Albert1 aHui, Jennie1 aHung, Joe1 aIsomaa, Bo1 aJohnson, Paul, R V1 aJørgensen, Torben1 aJula, Antti1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aLyssenko, Valeriya1 aMahley, Robert1 aMangino, Massimo1 aManning, Alisa, K1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcCulloch, Laura, J1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMorken, Mario, A1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNarisu, Narisu1 aNeville, Matthew, J1 aOostra, Ben, A1 aOrrù, Marco1 aPakyz, Ruth1 aPalmer, Colin, N A1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPerola, Markus1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRathmann, Wolfgang1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRoden, Michael1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aScott, Laura, J1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurethsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTanaka, Toshiko1 aThorand, Barbara1 aTichet, Jean1 aTönjes, Anke1 aTuomi, Tiinamaija1 aUitterlinden, André, G1 aDijk, Ko Willems1 aHoek, Mandy1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWalters, Bragi, G1 aWard, Kim, L1 aWatkins, Hugh1 aWeedon, Michael, N1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZeggini, Eleftheria1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aLoos, Ruth, J F1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aHattersley, Andrew, T1 aSilander, Kaisa1 aSalomaa, Veikko1 aSmith, George Davey1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aDedoussis, George, V1 aSerrano-Ríos, Manuel1 aMorris, Andrew, D1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPankow, James, S1 aSampson, Michael, J1 aKuusisto, Johanna1 aLaakso, Markku1 aHansen, Torben1 aPedersen, Oluf1 aPramstaller, Peter Paul1 aWichmann, Erich, H1 aIllig, Thomas1 aRudan, Igor1 aWright, Alan, F1 aStumvoll, Michael1 aCampbell, Harry1 aWilson, James, F1 aBergman, Richard, N1 aBuchanan, Thomas, A1 aCollins, Francis, S1 aMohlke, Karen, L1 aTuomilehto, Jaakko1 aValle, Timo, T1 aAltshuler, David1 aRotter, Jerome, I1 aSiscovick, David, S1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aDeloukas, Panos1 aSpector, Timothy, D1 aFrayling, Timothy, M1 aFerrucci, Luigi1 aKong, Augustine1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAulchenko, Yurii, S1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aWaterworth, Dawn, M1 aVollenweider, Peter1 aPeltonen, Leena1 aMooser, Vincent1 aAbecasis, Goncalo, R1 aWareham, Nicholas, J1 aSladek, Robert1 aFroguel, Philippe1 aWatanabe, Richard, M1 aMeigs, James, B1 aGroop, Leif1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aFlorez, Jose, C1 aBarroso, Inês1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal BPgen Consortium1 aAnders Hamsten on behalf of Procardis Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/116006326nas a2201873 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2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 aChronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118302243nas a2200361 4500008004100000022001400041245014200055210006900197260001300266300001100279490000700290520121600297653001601513653000901529653001501538653002001553653001901573653001101592653001101603653000901614653001601623653003001639653001701669653001401686653002601700653001201726653002401738100001701762700002301779700002301802700002001825856003601845 2010 eng d a0161-810500aA novel approach to prediction of mild obstructive sleep disordered breathing in a population-based sample: the Sleep Heart Health Study.0 anovel approach to prediction of mild obstructive sleep disordere c2010 Dec a1641-80 v333 aThis manuscript considers a data-mining approach for the prediction of mild obstructive sleep disordered breathing, defined as an elevated respiratory disturbance index (RDI), in 5,530 participants in a community-based study, the Sleep Heart Health Study. The prediction algorithm was built using modern ensemble learning algorithms, boosting in specific, which allowed for assessing potential high-dimensional interactions between predictor variables or classifiers. To evaluate the performance of the algorithm, the data were split into training and validation sets for varying thresholds for predicting the probability of a high RDI (≥7 events per hour in the given results). Based on a moderate classification threshold from the boosting algorithm, the estimated post-test odds of a high RDI were 2.20 times higher than the pre-test odds given a positive test, while the corresponding post-test odds were decreased by 52% given a negative test (sensitivity and specificity of 0.66 and 0.70, respectively). In rank order, the following variables had the largest impact on prediction performance: neck circumference, body mass index, age, snoring frequency, waist circumference, and snoring loudness.
10aAge Factors10aAged10aAlgorithms10aBody Mass Index10aCohort Studies10aFemale10aHumans10aMale10aMiddle Aged10aPredictive Value of Tests10aRisk Factors10aROC Curve10aSleep Apnea Syndromes10aSnoring10aWaist Circumference1 aCaffo, Brian1 aDiener-West, Marie1 aPunjabi, Naresh, M1 aSamet, Jonathan uhttps://chs-nhlbi.org/node/125204638nas a2200901 4500008004100000022001400041245020700055210006900262260001600331300001200347490000800359520199800367653001002365653001502375653001602390653001102406653003402417653001502451653001102466653000902477653001602486653001402502653003602516653001502552653002602567100002302593700002002616700001902636700002302655700001702678700002002695700002202715700001602737700002502753700001902778700002502797700001602822700001902838700001602857700002702873700002202900700002002922700002302942700002202965700002302987700002203010700002103032700002303053700002103076700002203097700002803119700001803147700002003165700002003185700002103205700001803226700002203244700002203266700002103288700001903309700002103328700002403349700001903373700002003392700001903412700002103431700002203452700002403474700002003498700002103518700002003539700001903559700003003578700001803608700003003626710004403656856003603700 2010 eng d a1524-453900aNovel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.0 aNovel associations of multiple genetic loci with plasma levels o c2010 Mar 30 a1382-920 v1213 aBACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.
METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.
CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
10aAdult10aFactor VII10aFactor VIII10aFemale10aGenome-Wide Association Study10aHemostasis10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aThrombosis10avon Willebrand Factor1 aSmith, Nicholas, L1 aChen, Ming-Huei1 aDehghan, Abbas1 aStrachan, David, P1 aBasu, Saonli1 aSoranzo, Nicole1 aHayward, Caroline1 aRudan, Igor1 aSabater-Lleal, Maria1 aBis, Joshua, C1 ade Maat, Moniek, P M1 aRumley, Ann1 aKong, Xiaoxiao1 aYang, Qiong1 aWilliams, Frances, M K1 aVitart, Veronique1 aCampbell, Harry1 aMälarstig, Anders1 aWiggins, Kerri, L1 aDuijn, Cornelia, M1 aMcArdle, Wendy, L1 aPankow, James, S1 aJohnson, Andrew, D1 aSilveira, Angela1 aMcKnight, Barbara1 aUitterlinden, André, G1 aAleksic, Nena1 aMeigs, James, B1 aPeters, Annette1 aKoenig, Wolfgang1 aCushman, Mary1 aKathiresan, Sekar1 aRotter, Jerome, I1 aBovill, Edwin, G1 aHofman, Albert1 aBoerwinkle, Eric1 aTofler, Geoffrey, H1 aPeden, John, F1 aPsaty, Bruce, M1 aLeebeek, Frank1 aFolsom, Aaron, R1 aLarson, Martin, G1 aSpector, Timothy, D1 aWright, Alan, F1 aWilson, James, F1 aHamsten, Anders1 aLumley, Thomas1 aWitteman, Jacqueline, C M1 aTang, Weihong1 aO'Donnell, Christopher, J1 aWellcome Trust Case Control Consortium; uhttps://chs-nhlbi.org/node/117602996nas a2200445 4500008004100000022001400041245009000055210006900145260001300214300001100227490000700238520178300245653000902028653002202037653001902059653001102078653003002089653001102119653001402130653002502144653000902169653001202178653003002190653000902220653001702229653001702246653002302263653002602286653001102312653002102323100002102344700001902365700002402384700002502408700002002433700002102453700001802474700002202492856003602514 2011 eng d a1524-462800aNeighborhood disadvantage and ischemic stroke: the Cardiovascular Health Study (CHS).0 aNeighborhood disadvantage and ischemic stroke the Cardiovascular c2011 Dec a3363-80 v423 aBACKGROUND AND PURPOSE: Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status and incident ischemic stroke and examine potential mediators of these associations.
METHODS: We analyzed data from 3834 whites and 785 blacks enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages≥65 years from 4 US counties. The primary outcome was adjudicated incident ischemic stroke. Neighborhood socioeconomic status was measured using a composite of 6 census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed adjusted for sociodemographic, behavioral, and biological risk factors.
RESULTS: Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared with the highest neighborhood socioeconomic status quartile (hazard ratio, 1.32; 95% CI, 1.01-1.72) with greater attenuation of the hazard ratio after adjustment for biological risk factors (hazard ratio, 1.16; 0.88-1.52) than for behavioral risk factors (hazard ratio, 1.30; 0.99-1.70). Among blacks, we found no significant associations between neighborhood socioeconomic status and ischemic stroke.
CONCLUSIONS: Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among blacks. The relationship between neighborhood socioeconomic status and stroke among whites appears to be mediated more strongly by biological than behavioral risk factors.
10aAged10aAged, 80 and over10aBrain Ischemia10aFemale10aHealth Status Disparities10aHumans10aIncidence10aLongitudinal Studies10aMale10aPoverty10aResidence Characteristics10aRisk10aRisk Factors10aSocial Class10aSocial Environment10aSocioeconomic Factors10aStroke10aUrban Population1 aBrown, Arleen, F1 aLiang, Li-Jung1 aVassar, Stefanie, D1 aStein-Merkin, Sharon1 aLongstreth, W T1 aOvbiagele, Bruce1 aYan, Tingjian1 aEscarce, José, J uhttps://chs-nhlbi.org/node/133207496nas a2202305 4500008004100000022001400041245006700055210006600122260001600188300001000204490000800214520114000222653001201362653002001374653001401394653002801408653002401436653001101460653003001471653001901501653001801520653003401538653001801572653001101590653001901601653001901620653002901639653002701668653001401695653002301709100002201732700002601754700001601780700001801796700002001814700002001834700002901854700001901883700002301902700001801925700002001943700001801963700002001981700002002001700002002021700002102041700002202062700001702084700001802101700002602119700001902145700002202164700002002186700002402206700002402230700001802254700002202272700001802294700001602312700002002328700002202348700002102370700001802391700002302409700001502432700002602447700002002473700002002493700002102513700002502534700001702559700002902576700001902605700001902624700002302643700002202666700002202688700002102710700001702731700001702748700002302765700001902788700002002807700001802827700002202845700002002867700001802887700001402905700002102919700001902940700002202959700002202981700001903003700002803022700002303050700002803073700001803101700001803119700002003137700002103157700001903178700002103197700003103218700002003249700002503269700001903294700002103313700002003334700002403354700002203378700001803400700002503418700002503443700002103468700002003489700001803509700002003527700001903547700002303566700001803589700002603607700001803633700001903651700002203670700002203692700001903714700001703733700002203750700002303772700002403795700002203819700002403841700001703865700002303882700002003905700001903925700002203944700002303966700002203989700001704011700001904028700002104047700001804068700001704086700001804103700002804121700002304149700001704172700002204189700002204211700002304233700001804256700002004274700001904294700002104313700002504334700002104359700002204380700002104402700001904423700002304442700002004465700002304485700002304508700001804531700001804549700002204567700002204589700002704611700002404638700002304662700002004685700002404705700002504729700002804754700001904782700002004801700002404821700001604845700002204861700001904883700002204902700002104924700002104945700001904966700002104985700002105006700001805027700002105045700002005066700002405086700002405110700002005134856003605154 2011 eng d a1476-468700aNew gene functions in megakaryopoiesis and platelet formation.0 aNew gene functions in megakaryopoiesis and platelet formation c2011 Nov 30 a201-80 v4803 aPlatelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
10aAnimals10aBlood Platelets10aCell Size10aDrosophila melanogaster10aDrosophila Proteins10aEurope10aGene Expression Profiling10aGene Silencing10aGenome, Human10aGenome-Wide Association Study10aHematopoiesis10aHumans10aMegakaryocytes10aPlatelet Count10aProtein Interaction Maps10aTranscription, Genetic10aZebrafish10aZebrafish Proteins1 aGieger, Christian1 aRadhakrishnan, Aparna1 aCvejic, Ana1 aTang, Weihong1 aPorcu, Eleonora1 aPistis, Giorgio1 aSerbanovic-Canic, Jovana1 aElling, Ulrich1 aGoodall, Alison, H1 aLabrune, Yann1 aLopez, Lorna, M1 aMägi, Reedik1 aMeacham, Stuart1 aOkada, Yukinori1 aPirastu, Nicola1 aSorice, Rossella1 aTeumer, Alexander1 aVoss, Katrin1 aZhang, Weihua1 aRamirez-Solis, Ramiro1 aBis, Joshua, C1 aEllinghaus, David1 aGögele, Martin1 aHottenga, Jouke-Jan1 aLangenberg, Claudia1 aKovacs, Peter1 aO'Reilly, Paul, F1 aShin, So-Youn1 aEsko, Tõnu1 aHartiala, Jaana1 aKanoni, Stavroula1 aMurgia, Federico1 aParsa, Afshin1 aStephens, Jonathan1 aHarst, Pim1 avan der Schoot, Ellen1 aAllayee, Hooman1 aAttwood, Antony1 aBalkau, Beverley1 aBastardot, François1 aBasu, Saonli1 aBaumeister, Sebastian, E1 aBiino, Ginevra1 aBomba, Lorenzo1 aBonnefond, Amélie1 aCambien, Francois1 aChambers, John, C1 aCucca, Francesco1 aD'Adamo, Pio1 aDavies, Gail1 ade Boer, Rudolf, A1 aGeus, Eco, J C1 aDöring, Angela1 aElliott, Paul1 aErdmann, Jeanette1 aEvans, David, M1 aFalchi, Mario1 aFeng, Wei1 aFolsom, Aaron, R1 aFrazer, Ian, H1 aGibson, Quince, D1 aGlazer, Nicole, L1 aHammond, Chris1 aHartikainen, Anna-Liisa1 aHeckbert, Susan, R1 aHengstenberg, Christian1 aHersch, Micha1 aIllig, Thomas1 aLoos, Ruth, J F1 aJolley, Jennifer1 aKhaw, Kay, Tee1 aKuhnel, Brigitte1 aKyrtsonis, Marie-Christine1 aLagou, Vasiliki1 aLloyd-Jones, Heather1 aLumley, Thomas1 aMangino, Massimo1 aMaschio, Andrea1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMemari, Yasin1 aMitchell, Braxton, D1 aMontgomery, Grant, W1 aNakamura, Yusuke1 aNauck, Matthias1 aNavis, Gerjan1 aNöthlings, Ute1 aNolte, Ilja, M1 aPorteous, David, J1 aPouta, Anneli1 aPramstaller, Peter, P1 aPullat, Janne1 aRing, Susan, M1 aRotter, Jerome, I1 aRuggiero, Daniela1 aRuokonen, Aimo1 aSala, Cinzia1 aSamani, Nilesh, J1 aSambrook, Jennifer1 aSchlessinger, David1 aSchreiber, Stefan1 aSchunkert, Heribert1 aScott, James1 aSmith, Nicholas, L1 aSnieder, Harold1 aStarr, John, M1 aStumvoll, Michael1 aTakahashi, Atsushi1 aTang, W, H Wilson1 aTaylor, Kent1 aTenesa, Albert1 aThein, Swee, Lay1 aTönjes, Anke1 aUda, Manuela1 aUlivi, Sheila1 avan Veldhuisen, Dirk, J1 aVisscher, Peter, M1 aVölker, Uwe1 aWichmann, H-Erich1 aWiggins, Kerri, L1 aWillemsen, Gonneke1 aYang, Tsun-Po1 aZhao, Jing, Hua1 aZitting, Paavo1 aBradley, John, R1 aDedoussis, George, V1 aGasparini, Paolo1 aHazen, Stanley, L1 aMetspalu, Andres1 aPirastu, Mario1 aShuldiner, Alan, R1 avan Pelt, Joost1 aZwaginga, Jaap-Jan1 aBoomsma, Dorret, I1 aDeary, Ian, J1 aFranke, Andre1 aFroguel, Philippe1 aGanesh, Santhi, K1 aJarvelin, Marjo-Riitta1 aMartin, Nicholas, G1 aMeisinger, Christa1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aWareham, Nicholas, J1 aAkkerman, Jan-Willem, N1 aCiullo, Marina1 aDeloukas, Panos1 aGreinacher, Andreas1 aJupe, Steve1 aKamatani, Naoyuki1 aKhadake, Jyoti1 aKooner, Jaspal, S1 aPenninger, Josef1 aProkopenko, Inga1 aStemple, Derek1 aToniolo, Daniela1 aWernisch, Lorenz1 aSanna, Serena1 aHicks, Andrew, A1 aRendon, Augusto1 aFerreira, Manuel, A1 aOuwehand, Willem, H1 aSoranzo, Nicole uhttps://chs-nhlbi.org/node/135503344nas a2200517 4500008004100000022001400041245014800055210006900203260001600272300001100288490000800299520172900307653002602036653003402062653001802096653003202114653002502146653003402171653001102205653003302216653003102249653005202280653001402332653001902346653002002365653001702385653001802402100002002420700002302440700001902463700002802482700002102510700002202531700002702553700001902580700002402599700002202623700002102645700001902666700001902685700002402704700002302728700002402751710001502775856003602790 2011 eng d a1476-625600aThe Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study.0 aNext PAGE in understanding complex traits design for the analysi c2011 Oct 01 a849-590 v1743 aGenetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.
10aEpidemiologic Methods10aEpidemiologic Research Design10aEthnic Groups10aGenetic Association Studies10aGenetics, Population10aGenome-Wide Association Study10aHumans10aInterinstitutional Relations10aMultifactorial Inheritance10aNational Human Genome Research Institute (U.S.)10aPhenotype10aPilot Projects10aResearch Design10aRisk Factors10aUnited States1 aMatise, Tara, C1 aAmbite, Jose, Luis1 aBuyske, Steven1 aCarlson, Christopher, S1 aCole, Shelley, A1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aHeiss, Gerardo1 aKooperberg, Charles1 aLe Marchand, Loic1 aManolio, Teri, A1 aNorth, Kari, E1 aPeters, Ulrike1 aRitchie, Marylyn, D1 aHindorff, Lucia, A1 aHaines, Jonathan, L1 aPAGE Study uhttps://chs-nhlbi.org/node/131303416nas a2200445 4500008004100000022001400041245015400055210006900209260000900278300001100287490000600298520209200304653001502396653001002411653002202421653001002443653004302453653001702496653002402513653001402537653003102551653001102582653002202593653002602615653001402641653000902655653004502664653001402709653002102723653002502744653001602769100002102785700002002806700002302826700001902849700002202868700002402890700002002914856003602934 2011 eng d a1932-620300aNK-like T cells and plasma cytokines, but not anti-viral serology, define immune fingerprints of resilience and mild disability in exceptional aging.0 aNKlike T cells and plasma cytokines but not antiviral serology d c2011 ae265580 v63 aExceptional aging has been defined as maintenance of physical and cognitive function beyond the median lifespan despite a history of diseases and/or concurrent subclinical conditions. Since immunity is vital to individual fitness, we examined immunologic fingerprint(s) of highly functional elders. Therefore, survivors of the Cardiovascular Health Study in Pittsburgh, Pennsylvania, USA were recruited (n = 140; mean age = 86 years) and underwent performance testing. Blood samples were collected and examined blindly for humoral factors and T cell phenotypes. Based on results of physical and cognitive performance testing, elders were classified as "impaired" or "unimpaired", accuracy of group assignment was verified by discriminant function analysis. The two groups showed distinct immune profiles as determined by factor analysis. The dominant immune signature of impaired elders consisted of interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor-α, and T cells expressing inhibitory natural killer-related receptors (NKR) CD158a, CD158e, and NKG2A. In contrast, the dominant signature of unimpaired elders consisted of IL-5, IL-12p70, and IL-13 with co-expression of IFN-γ, IL-4, and IL-17, and T cells expressing stimulatory NKRs CD56, CD16, and NKG2D. In logistic regression models, unimpaired phenotype was predicted independently by IL-5 and by CD4(+)CD28(null)CD56(+)CD57(+) T cells. All elders had high antibody titers to common viruses including cytomegalovirus. In cellular bioassays, T cell receptor (TCR)-independent ligation of either CD56 or NKG2D elicited activation of T cells. Collectively, these data demonstrate the importance of immunological parameters in distinguishing between health phenotypes of older adults. NKR(+) T cells and cytokine upregulation indicate a unique physiologic environment in old age. Correlation of particular NKR(+) T cell subsets and IL-5 with unimpaired performance, and NKR-driven TCR-independent activation of T cells suggest novel immunopathway(s) that could be exploited to improve immunity in old age.
10aAdolescent10aAdult10aAged, 80 and over10aAging10aCardiovascular Physiological Phenomena10aCD56 Antigen10aCognition Disorders10aCytokines10aGene Expression Regulation10aHumans10aImmunity, Humoral10aKiller Cells, Natural10aLongevity10aMale10aNK Cell Lectin-Like Receptor Subfamily K10aPhenotype10aPhysical Fitness10aT-Lymphocyte Subsets10aYoung Adult1 aVallejo, Abbe, N1 aHamel, David, L1 aMueller, Robert, G1 aIves, Diane, G1 aMichel, Joshua, J1 aBoudreau, Robert, M1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/134603083nas a2200469 4500008004100000022001400041245012500055210006900180260001300249300001100262490000600273520170600279653002101985653000902006653001502015653002802030653001902058653002502077653002702102653001102129653001102140653001402151653002602165653000902191653001602200653003102216653002202247653003002269653003202299653002602331653002002357653002102377653001702398653001802415100002302433700002202456700002702478700002402505700002402529700002402553856003602577 2011 eng d a1556-387100aN-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study.0 aNterminal proBtype natriuretic peptide is associated with sudden c2011 Feb a228-330 v83 aBACKGROUND: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women.
OBJECTIVE: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
METHODS: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP.
RESULTS: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95% confidence interval [1.6, 3.8]; P <.001).
CONCLUSION: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
10aAge Distribution10aAged10aBiomarkers10aCardiovascular Diseases10aCohort Studies10aConfidence Intervals10aDeath, Sudden, Cardiac10aFemale10aHumans10aIncidence10aKaplan-Meier Estimate10aMale10aMiddle Aged10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aProportional Hazards Models10aRetrospective Studies10aRisk Assessment10aSex Distribution10aTime Factors10aUnited States1 aPatton, Kristen, K1 aSotoodehnia, Nona1 aDeFilippi, Christopher1 aSiscovick, David, S1 aGottdiener, John, S1 aKronmal, Richard, A uhttps://chs-nhlbi.org/node/124203060nas a2200421 4500008004100000022001400041245010300055210006900158260001300227300001100240490000700251520187200258653002102130653000902151653002202160653001902182653002802201653001902229653002402248653001102272653001102283653001902294653002202313653002002335653002502355653000902380653001502389653001702404653003002421653003002451653002102481653001602502100002102518700002102539700002102560700002102581856003602602 2012 eng d a1945-719700aThe natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study.0 anatural history of subclinical hypothyroidism in the elderly the c2012 Jun a1962-90 v973 aCONTEXT: Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time.
OBJECTIVE: We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex.
DESIGN, SETTING, AND PARTICIPANTS: Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication.
MAIN OUTCOME MEASURE: Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex.
RESULTS: Persistence of subclinical hypothyroidism was 56% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10% with TSH 7-9.9 mU/liter and 7% with TSH ≥10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions.
CONCLUSIONS: Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes.
10aAge Distribution10aAged10aAged, 80 and over10aAutoantibodies10aCardiovascular Diseases10aCohort Studies10aDisease Progression10aFemale10aHumans10aHypothyroidism10aIodide Peroxidase10aLogistic Models10aLongitudinal Studies10aMale10aPrevalence10aRisk Factors10aSeroepidemiologic Studies10aSeverity of Illness Index10aSex Distribution10aThyrotropin1 aSomwaru, Lily, L1 aRariy, Chevon, M1 aArnold, Alice, M1 aCappola, Anne, R uhttps://chs-nhlbi.org/node/137302907nas a2200325 4500008004100000022001400041245010000055210006900155260000900224300001100233490000600244520199600250653000902246653002802255653002802283653001102311653001102322653000902333653001602342653001302358653002002371653002602391100002602417700002402443700002202467700001602489700002002505700002002525856003602545 2012 eng d a1932-620300aNocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort.0 aNocturia sleepdisordered breathing and cardiovascular morbidity c2012 ae309690 v73 aBACKGROUND: Nocturia has been independently associated with cardiovascular morbidity and all-cause mortality, but such studies did not adjust for sleep-disordered breathing (SDB), which may have mediated such a relationship. Our aims were to determine whether an association between nocturia and cardiovascular morbidity exists that is independent of SDB. We also determined whether nocturia is independently associated with SDB.
METHODOLOGY/PRINCIPAL FINDINGS: In order to accomplish these aims we performed a cross-sectional analysis of the Sleep Heart Health Study that contained information regarding SDB, nocturia, and cardiovascular morbidity in a middle-age to elderly community-based population. In 6342 participants (age 63±11 [SD] years, 53% women), after adjusting for known confounders such as age, body mass index, diuretic use, diabetes mellitus, alpha-blocker use, nocturia was independently associated with SDB (measured as Apnea Hypopnea index >15 per hour; OR 1.3; 95%CI, 1.2-1.5). After adjusting for SDB and other known confounders, nocturia was independently associated with prevalent hypertension (OR 1.23; 95%CI 1.08-1.40; P = 0.002), cardiovascular disease (OR 1.26; 95%CI 1.05-1.52; P = 0.02) and stroke (OR 1.62; 95%CI 1.14-2.30; P = 0.007). Moreover, nocturia was also associated with adverse objective alterations of sleep as measured by polysomnography and self-reported excessive daytime sleepiness (P<0.05).
CONCLUSIONS/SIGNIFICANCE: Nocturia is independently associated with sleep-disordered breathing. After adjusting for SDB, there remained an association between nocturia and cardiovascular morbidity. Such results support screening for SDB in patients with nocturia, but the mechanisms underlying the relationship between nocturia and cardiovascular morbidity requires further study. MeSH terms: Nocturia, sleep-disordered breathing, obstructive sleep apnea, sleep apnea, polysomnography, hypertension.
10aAged10aCardiovascular Diseases10aCross-Sectional Studies10aFemale10aHumans10aMale10aMiddle Aged10aNocturia10aPolysomnography10aSleep Apnea Syndromes1 aParthasarathy, Sairam1 aFitzgerald, MaryPat1 aGoodwin, James, L1 aUnruh, Mark1 aGuerra, Stefano1 aQuan, Stuart, F uhttps://chs-nhlbi.org/node/155802821nas a2200433 4500008004100000022001400041245008000055210006900135260001300204300001000217490000600227520161000233653000901843653002201852653001501874653002701889653003101916653001101947653002201958653001101980653001401991653000902005653003202014653002402046653002602070653001702096100001802113700001902131700001902150700002002169700002402189700002202213700002102235700002502256700002202281700002402303700002402327856003602351 2012 eng d a1941-308400aNonesterified fatty acids and risk of sudden cardiac death in older adults.0 aNonesterified fatty acids and risk of sudden cardiac death in ol c2012 Apr a273-80 v53 aBACKGROUND: Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.
METHODS AND RESULTS: Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.
CONCLUSIONS: Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.
10aAged10aAged, 80 and over10aBiomarkers10aDeath, Sudden, Cardiac10aFatty Acids, Nonesterified10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aProportional Hazards Models10aProspective Studies10aRetrospective Studies10aRisk Factors1 aDjoussé, Luc1 aBiggs, Mary, L1 aIx, Joachim, H1 aKizer, Jorge, R1 aLemaitre, Rozenn, N1 aSotoodehnia, Nona1 aZieman, Susan, J1 aMozaffarian, Dariush1 aTracy, Russell, P1 aMukamal, Kenneth, J1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/136103386nas a2200505 4500008004100000022001400041245011100055210006900166260001300235300001200248490000700260520193600267653000902203653002202212653001502234653002802249653001902277653002802296653002402324653001102348653002202359653001102381653001402392653002502406653000902431653001602440653002402456653003302480653003202513653002402545653001702569653001102586653002202597653001802619100002102637700002402658700001902682700001902701700002702720700002302747700002502770700002402795700002502819856003602844 2012 eng d a1938-320700aNovel circulating fatty acid patterns and risk of cardiovascular disease: the Cardiovascular Health Study.0 aNovel circulating fatty acid patterns and risk of cardiovascular c2012 Dec a1252-610 v963 aBACKGROUND: Complex interplays of diet and metabolism influence circulating fatty acids (FAs), possibly constituting FA patterns related to cardiovascular disease (CVD) risk.
OBJECTIVES: We aimed to derive FA patterns from circulating FAs, relate the patterns to CVD incidence, and extend the derived patterns to atherosclerosis progression in another independent cohort.
DESIGN: We used principal component analysis (PCA) to derive FA patterns from 38 plasma phospholipid FAs in 2972 older adults in the Cardiovascular Health Study (CHS). Identified patterns were evaluated for prospective associations with 14-y incidence of CVD [ischemic heart disease (IHD) or stroke]. In another independent cohort of postmenopausal women with IHD, we evaluated associations of the CHS-derived patterns with 3.2-y progression of angiographically defined coronary atherosclerosis.
RESULTS: Three distinct patterns were identified, characterized by higher proportions of trans FAs, de novo lipogenesis (DNL) FAs, and long-chain MUFAs (LCMUFAs). During 32,265 person-years, 780 incident CVD events occurred. The trans FA pattern was associated with higher CVD risk (multivariable-adjusted HR for the highest compared with the lowest quintiles = 1.58; 95% CI: 1.17, 2.12; P-trend = 0.006), primarily attributable to higher risk of stroke (HR: 2.46; 95% CI: 1.54, 3.92; P-trend = 0.005). The DNL and LCMUFA patterns were not associated with CVD incidence or with IHD or stroke (P-trend > 0.11 each). In the second cohort, the trans FA pattern, but not the other 2 patterns, was positively associated with progression of coronary atherosclerosis (P-trend < 0.05).
CONCLUSIONS: PCA appears to provide informative circulating FA patterns. A pattern driven mainly by trans FA levels related to greater CVD risk in older adults and coronary atherosclerosis progression in women with IHD.
10aAged10aAged, 80 and over10aBiomarkers10aCardiovascular Diseases10aCohort Studies10aCoronary Artery Disease10aDisease Progression10aFemale10aFollow-Up Studies10aHumans10aIncidence10aLongitudinal Studies10aMale10aMiddle Aged10aMyocardial Ischemia10aPrincipal Component Analysis10aProportional Hazards Models10aProspective Studies10aRisk Factors10aStroke10aTrans Fatty Acids10aUnited States1 aImamura, Fumiaki1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aSong, Xiaoling1 aLichtenstein, Alice, H1 aMatthan, Nirupa, R1 aHerrington, David, M1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/141004310nas a2200901 4500008004100000022001400041245011000055210006900165260001300234300001100247490000600258520179200264653001002056653002202066653001902088653002402107653001102131653001702142653003402159653001102193653000902204653002702213653001602240653003602256100002002292700001702312700002102329700002202350700001902372700002002391700001202411700002202423700002102445700001902466700001902485700002402504700002402528700001702552700001402569700001502583700002402598700002302622700001902645700001902664700002402683700002202707700001202729700002402741700001702765700002202782700002602804700001702830700001702847700002002864700002902884700001902913700002302932700002002955700002102975700001902996700002003015700002203035700002403057700002403081700002503105700001803130700002403148700002803172700002003200700002303220700002003243700002103263700002203284700002203306700002203328700002203350856003603372 2012 eng d a1942-326800aNovel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.0 aNovel loci associated with PR interval in a genomewide associati c2012 Dec a639-460 v53 aBACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.
METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).
CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
10aAdult10aAfrican Americans10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide1 aButler, Anne, M1 aYin, Xiaoyan1 aEvans, Daniel, S1 aNalls, Michael, A1 aSmith, Erin, N1 aTanaka, Toshiko1 aLi, Guo1 aBuxbaum, Sarah, G1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBerenson, Gerald, S1 aBis, Josh, C1 aChen, Wei1 aDeo, Rajat1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHsueh, Wen-Chi1 aKeating, Brendan, J1 aKerr, Kathleen, F1 aLi, Yun1 aLimacher, Marian, C1 aLiu, Yongmei1 aLubitz, Steven, A1 aMarciante, Kristin, D1 aMehra, Reena1 aMeng, Yan, A1 aNewman, Anne, B1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPalmer, Cameron, D1 aPsaty, Bruce, M1 aQuibrera, Miguel1 aRedline, Susan1 aReiner, Alex, P1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aFerrucci, Luigi1 aMurray, Sarah, S1 aEvans, Michele, K1 aSotoodehnia, Nona1 aMagnani, Jared, W1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/608421848nas a2207177 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2012 eng d a1553-740400aNovel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.0 aNovel loci for adiponectin levels and their influence on type 2 c2012 ae10026070 v83 aCirculating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
10aAdiponectin10aAfrican Americans10aAsian Continental Ancestry Group10aCholesterol, HDL10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Expression10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Tolerance Test10aHumans10aInsulin Resistance10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aDastani, Zari1 aHivert, Marie-France1 aTimpson, Nicholas1 aPerry, John, R B1 aYuan, Xin1 aScott, Robert, A1 aHenneman, Peter1 aHeid, Iris, M1 aKizer, Jorge, R1 aLyytikäinen, Leo-Pekka1 aFuchsberger, Christian1 aTanaka, Toshiko1 aMorris, Andrew, P1 aSmall, Kerrin1 aIsaacs, Aaron1 aBeekman, Marian1 aCoassin, Stefan1 aLohman, Kurt1 aQi, Lu1 aKanoni, Stavroula1 aPankow, James, S1 aUh, Hae-Won1 aWu, Ying1 aBidulescu, Aurelian1 aRasmussen-Torvik, Laura, J1 aGreenwood, Celia, M T1 aLadouceur, Martin1 aGrimsby, Jonna1 aManning, Alisa, K1 aLiu, Ching-Ti1 aKooner, Jaspal1 aMooser, Vincent, E1 aVollenweider, Peter1 aKapur, Karen, A1 aChambers, John1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aFrants, Rune1 aWillems-Vandijk, Ko1 aOostra, Ben, A1 aWillems, Sara, M1 aLamina, Claudia1 aWinkler, Thomas, W1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBrody, Jennifer1 aChen, Ida1 aViikari, Jorma1 aKähönen, Mika1 aPramstaller, Peter, P1 aEvans, David, M1 aSt Pourcain, Beate1 aSattar, Naveed1 aWood, Andrew, R1 aBandinelli, Stefania1 aCarlson, Olga, D1 aEgan, Josephine, M1 aBöhringer, Stefan1 avan Heemst, Diana1 aKedenko, Lyudmyla1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aLoo, Britt-Marie1 aHarris, Tamara1 aGarcia, Melissa1 aKanaya, Alka1 aHaun, Margot1 aKlopp, Norman1 aWichmann, H-Erich1 aDeloukas, Panos1 aKatsareli, Efi1 aCouper, David, J1 aDuncan, Bruce, B1 aKloppenburg, Margreet1 aAdair, Linda, S1 aBorja, Judith, B1 aWilson, James, G1 aMusani, Solomon1 aGuo, Xiuqing1 aJohnson, Toby1 aSemple, Robert1 aTeslovich, Tanya, M1 aAllison, Matthew, A1 aRedline, Susan1 aBuxbaum, Sarah, G1 aMohlke, Karen, L1 aMeulenbelt, Ingrid1 aBallantyne, Christie, M1 aDedoussis, George, V1 aHu, Frank, B1 aLiu, Yongmei1 aPaulweber, Bernhard1 aSpector, Timothy, D1 aSlagboom, Eline1 aFerrucci, Luigi1 aJula, Antti1 aPerola, Markus1 aRaitakari, Olli1 aFlorez, Jose, C1 aSalomaa, Veikko1 aEriksson, Johan, G1 aFrayling, Timothy, M1 aHicks, Andrew, A1 aLehtimäki, Terho1 aSmith, George Davey1 aSiscovick, David, S1 aKronenberg, Florian1 aDuijn, Cornelia1 aLoos, Ruth, J F1 aWaterworth, Dawn, M1 aMeigs, James, B1 aDupuis, Josée1 aRichards, Brent1 aVoight, Benjamin, F1 aScott, Laura, J1 aSteinthorsdottir, Valgerdur1 aDina, Christian1 aWelch, Ryan, P1 aZeggini, Eleftheria1 aHuth, Cornelia1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aMcCulloch, Laura, J1 aFerreira, Teresa1 aGrallert, Harald1 aAmin, Najaf1 aWu, Guanming1 aWiller, Cristen, J1 aRaychaudhuri, Soumya1 aMcCarroll, Steve, A1 aHofmann, Oliver, M1 aSegrè, Ayellet, V1 aHoek, Mandy1 aNavarro, Pau1 aArdlie, Kristin1 aBalkau, Beverley1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBlagieva, Roza1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBoström, Kristina, Bengtsson1 aBravenboer, Bert1 aBumpstead, Suzannah1 aBurtt, Noel, P1 aCharpentier, Guillaume1 aChines, Peter, S1 aCornelis, Marilyn1 aCrawford, Gabe1 aDoney, Alex, S F1 aElliott, Katherine, S1 aElliott, Amanda, L1 aErdos, Michael, R1 aFox, Caroline, S1 aFranklin, Christopher, S1 aGanser, Martha1 aGieger, Christian1 aGrarup, Niels1 aGreen, Todd1 aGriffin, Simon1 aGroves, Christopher, J1 aGuiducci, Candace1 aHadjadj, Samy1 aHassanali, Neelam1 aHerder, Christian1 aIsomaa, Bo1 aJackson, Anne, U1 aJohnson, Paul, R V1 aJørgensen, Torben1 aKao, Wen, H L1 aKong, Augustine1 aKraft, Peter1 aKuusisto, Johanna1 aLauritzen, Torsten1 aLi, Man1 aLieverse, Aloysius1 aLindgren, Cecilia, M1 aLyssenko, Valeriya1 aMarre, Michel1 aMeitinger, Thomas1 aMidthjell, Kristian1 aMorken, Mario, A1 aNarisu, Narisu1 aNilsson, Peter1 aOwen, Katharine, R1 aPayne, Felicity1 aPetersen, Ann-Kristin1 aPlatou, Carl1 aProença, Christine1 aProkopenko, Inga1 aRathmann, Wolfgang1 aRayner, William1 aRobertson, Neil, R1 aRocheleau, Ghislain1 aRoden, Michael1 aSampson, Michael, J1 aSaxena, Richa1 aShields, Beverley, M1 aShrader, Peter1 aSigurdsson, Gunnar1 aSparsø, Thomas1 aStrassburger, Klaus1 aStringham, Heather, M1 aSun, Qi1 aSwift, Amy, J1 aThorand, Barbara1 aTichet, Jean1 aTuomi, Tiinamaija1 avan Dam, Rob, M1 avan Haeften, Timon, W1 avan Herpt, Thijs1 avan Vliet-Ostaptchouk, Jana, V1 aWalters, Bragi, G1 aWeedon, Michael, N1 aWijmenga, Cisca1 aWitteman, Jacqueline1 aBergman, Richard, N1 aCauchi, Stephane1 aCollins, Francis, S1 aGloyn, Anna, L1 aGyllensten, Ulf1 aHansen, Torben1 aHide, Winston, A1 aHitman, Graham, A1 aHofman, Albert1 aHunter, David, J1 aHveem, Kristian1 aLaakso, Markku1 aMorris, Andrew, D1 aPalmer, Colin, N A1 aRudan, Igor1 aSijbrands, Eric1 aStein, Lincoln, D1 aTuomilehto, Jaakko1 aUitterlinden, Andre1 aWalker, Mark1 aWatanabe, Richard, M1 aAbecasis, Goncalo, R1 aBoehm, Bernhard, O1 aCampbell, Harry1 aDaly, Mark, J1 aHattersley, Andrew, T1 aPedersen, Oluf1 aBarroso, Inês1 aGroop, Leif1 aSladek, Rob1 aThorsteinsdottir, Unnur1 aWilson, James, F1 aIllig, Thomas1 aFroguel, Philippe1 aDuijn, Cornelia, M1 aStefansson, Kari1 aAltshuler, David1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aSoranzo, Nicole1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aMägi, Reedik1 aRandall, Joshua1 aElliott, Paul1 aRybin, Denis1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aSong, Kijoung1 aGoel, Anuj1 aLajunen, Taina1 aDoney, Alex1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aTimpson, Nicholas, J1 aZabena, Carina1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aAriyurek, Yavuz1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBergmann, Sven1 aBochud, Murielle1 aBonnefond, Amélie1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGrundy, Scott1 aGwilliam, Rhian1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHillman, David, R1 aHingorani, Aroon, D1 aHui, Jennie1 aHung, Joe1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aMahley, Robert1 aMangino, Massimo1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNeville, Matthew, J1 aOrrù, Marco1 aPakyz, Ruth1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurðsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTönjes, Anke1 aUitterlinden, André, G1 aDijk, Ko Willems1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWard, Kim, L1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aSilander, Kaisa1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aSerrano-Ríos, Manuel1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPramstaller, Peter Paul1 aWright, Alan, F1 aStumvoll, Michael1 aHamsten, Anders1 aBuchanan, Thomas, A1 aValle, Timo, T1 aRotter, Jerome, I1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aPeltonen, Leena1 aMooser, Vincent1 aSladek, Robert1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aChasman, Daniel, I1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aFeitosa, Mary, F1 aOrho-Melander, Marju1 aMelander, Olle1 aLi, Xiaohui1 aLi, Mingyao1 aCho, Yoon Shin1 aGo, Min Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWhitfield, John, B1 aThompson, John, R1 aSurakka, Ida1 aSpector, Tim, D1 aSmit, Johannes, H1 aSinisalo, Juha1 aScott, James1 aSaharinen, Juha1 aSabatti, Chiara1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aParker, Alex, N1 aParé, Guillaume1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aLucas, Gavin1 aLuben, Robert1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaplan, Lee, M1 aJohansson, Asa1 aJanssens, Cecile, J W1 aIgl, Wilmar1 aHovingh, Kees1 aHengstenberg, Christian1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGroop, Leif, C1 aGonzalez, Elena1 aFreimer, Nelson, B1 aErdmann, Jeanette1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 ade Faire, Ulf1 aCrawford, Gabriel1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aBoekholdt, Matthijs1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aTaylor, Herman, A1 aGabriel, Stacey, B1 aHolm, Hilma1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aStrachan, David, P1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aKathiresan, Sekar1 aDIAGRAM+ Consortium1 aMAGIC Consortium1 aGLGC Investigators1 aMuTHER Consortium1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal B Pgen Consortium1 aProcardis Consortium1 aMAGIC investigators1 aGLGC Consortium uhttps://chs-nhlbi.org/node/137802906nas a2200373 4500008004100000022001400041245007200055210006900127260001600196300001000212490000700222520187300229653000902102653001102111653001102122653001402133653002602147653000902173653003202182653003002214653001702244653002602261653001102287653002702298100002102325700001902346700002402365700002602389700002002415700002102435700001802456700002202474856003602496 2013 eng d a1526-632X00aNeighborhood socioeconomic disadvantage and mortality after stroke.0 aNeighborhood socioeconomic disadvantage and mortality after stro c2013 Feb 05 a520-70 v803 aOBJECTIVE: Residence in a socioeconomically disadvantaged community is associated with mortality, but the mechanisms are not well understood. We examined whether socioeconomic features of the residential neighborhood contribute to poststroke mortality and whether neighborhood influences are mediated by traditional behavioral and biologic risk factors.
METHODS: We used data from the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ≥65 years. Residential neighborhood disadvantage was measured using neighborhood socioeconomic status (NSES), a composite of 6 census tract variables representing income, education, employment, and wealth. Multilevel Cox proportional hazard models were constructed to determine the association of NSES to mortality after an incident stroke, adjusted for sociodemographic characteristics, stroke type, and behavioral and biologic risk factors.
RESULTS: Among the 3,834 participants with no prior stroke at baseline, 806 had a stroke over a mean 11.5 years of follow-up, with 168 (20%) deaths 30 days after stroke and 276 (34%) deaths at 1 year. In models adjusted for demographic characteristics, stroke type, and behavioral and biologic risk factors, mortality hazard 1 year after stroke was significantly higher among residents of neighborhoods with the lowest NSES than those in the highest NSES neighborhoods (hazard ratio 1.77, 95% confidence interval 1.17-2.68).
CONCLUSION: Living in a socioeconomically disadvantaged neighborhood is associated with higher mortality hazard at 1 year following an incident stroke. Further work is needed to understand the structural and social characteristics of neighborhoods that may contribute to mortality in the year after a stroke and the pathways through which these characteristics operate.
10aAged10aFemale10aHumans10aIncidence10aKaplan-Meier Estimate10aMale10aProportional Hazards Models10aResidence Characteristics10aRisk Factors10aSocioeconomic Factors10aStroke10aVulnerable Populations1 aBrown, Arleen, F1 aLiang, Li-Jung1 aVassar, Stefanie, D1 aMerkin, Sharon, Stein1 aLongstreth, W T1 aOvbiagele, Bruce1 aYan, Tingjian1 aEscarce, José, J uhttps://chs-nhlbi.org/node/585502686nas a2200697 4500008004100000022001400041245012800055210006900183260001300252300001200265490000800277520066900285653002100954653002100975653001900996653001801015653001101033653001901044653003301063653002501096653003401121653001101155653002101166653000901187653003601196653001501232653001201247653001801259653001601277100002201293700001901315700002301334700002301357700002101380700002101401700002801422700002201450700002301472700002101495700001901516700002101535700002401556700001601580700002201596700002201618700002201640700002601662700002301688700002101711700002101732700002301753700002201776700002301798700002701821700001901848700002401867700001901891700002001910700002201930856003601952 2013 eng d a1432-120300aNo evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population.0 aNo evidence of interaction between known lipidassociated genetic c2013 Dec a1427-310 v1323 aGenome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aEthnic Groups10aFemale10aGene Frequency10aGene-Environment Interaction10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aMale10aPolymorphism, Single Nucleotide10aPrevalence10aSmoking10aTriglycerides10aYoung Adult1 aDumitrescu, Logan1 aCarty, Cara, L1 aFranceschini, Nora1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBůzková, Petra1 aSchumacher, Fredrick, R1 aEaton, Charles, B1 aGoodloe, Robert, J1 aDuggan, David, J1 aHaessler, Jeff1 aCochran, Barbara1 aHenderson, Brian, E1 aCheng, Iona1 aJohnson, Karen, C1 aCarlson, Chris, S1 aLove, Shelly-Anne1 aBrown-Gentry, Kristin1 aNato, Alejandro, Q1 aQuibrera, Miguel1 aShohet, Ralph, V1 aAmbite, Jose, Luis1 aWilkens, Lynne, R1 aLe Marchand, Loïc1 aHaiman, Christopher, A1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aFornage, Myriam1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/629205936nas a2201453 4500008004100000022001400041245016600055210006900221260000900290300001200299490000600311520182200317653002102139653002002160653001502180653003302195653001302228653001102241653001202252100001802264700001502282700002202297700002502319700002202344700001902366700002002385700002002405700002002425700002202445700001802467700002402485700002302509700002402532700002002556700001602576700002002592700002202612700002502634700002902659700001902688700001702707700001602724700002002740700002402760700002502784700001802809700001802827700001902845700001802864700002102882700002002903700001502923700001802938700003002956700002102986700001703007700002003024700001903044700001903063700003003082700002503112700001903137700001703156700002403173700001803197700001903215700001803234700002203252700001403274700001903288700002403307700002103331700002703352700001803379700002603397700001903423700002403442700002303466700002803489700002603517700002303543700002303566700002103589700002003610700002603630700002003656700002103676700002503697700002503722700001703747700002103764700001903785700002403804700002203828700002103850700002103871700001903892700001503911700002003926700001903946700002103965700002803986700002004014700001704034700002504051700002004076700002304096700001904119700001904138700002004157700002104177700001904198700001904217700002004236700001904256700001804275700002504293700003204318700003004350700002304380700002004403700002304423856003604446 2014 eng d a1932-620300aNo evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.0 aNo evidence for genomewide interactions on plasma fibrinogen by c2014 ae1111560 v93 aPlasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
10aAlcohol Drinking10aBody Mass Index10aFibrinogen10aGene-Environment Interaction10aGenomics10aHumans10aSmoking1 aBaumert, Jens1 aHuang, Jie1 aMcKnight, Barbara1 aSabater-Lleal, Maria1 aSteri, Maristella1 aChu, Audrey, Y1 aTrompet, Stella1 aLopez, Lorna, M1 aFornage, Myriam1 aTeumer, Alexander1 aTang, Weihong1 aRudnicka, Alicja, R1 aMälarstig, Anders1 aHottenga, Jouke-Jan1 aKavousi, Maryam1 aLahti, Jari1 aTanaka, Toshiko1 aHayward, Caroline1 aHuffman, Jennifer, E1 aMorange, Pierre-Emmanuel1 aRose, Lynda, M1 aBasu, Saonli1 aRumley, Ann1 aStott, David, J1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aSanna, Serena1 aMasala, Marco1 aBiffar, Reiner1 aHomuth, Georg1 aSilveira, Angela1 aSennblad, Bengt1 aGoel, Anuj1 aWatkins, Hugh1 aMüller-Nurasyid, Martina1 aRückerl, Regina1 aTaylor, Kent1 aChen, Ming-Huei1 aGeus, Eco, J C1 aHofman, Albert1 aWitteman, Jacqueline, C M1 ade Maat, Moniek, P M1 aPalotie, Aarno1 aDavies, Gail1 aSiscovick, David, S1 aKolcic, Ivana1 aWild, Sarah, H1 aSong, Jaejoon1 aMcArdle, Wendy, L1 aFord, Ian1 aSattar, Naveed1 aSchlessinger, David1 aGrotevendt, Anne1 aFranzosi, Maria Grazia1 aIllig, Thomas1 aWaldenberger, Melanie1 aLumley, Thomas1 aTofler, Geoffrey, H1 aWillemsen, Gonneke1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aRäikkönen, Katri1 aChasman, Daniel, I1 aFolsom, Aaron, R1 aLowe, Gordon, D1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aCucca, Francesco1 aWallaschofski, Henri1 aStrawbridge, Rona, J1 aSeedorf, Udo1 aKoenig, Wolfgang1 aBis, Joshua, C1 aMukamal, Kenneth, J1 avan Dongen, Jenny1 aWiden, Elisabeth1 aFranco, Oscar, H1 aStarr, John, M1 aLiu, Kiang1 aFerrucci, Luigi1 aPolasek, Ozren1 aWilson, James, F1 aOudot-Mellakh, Tiphaine1 aCampbell, Harry1 aNavarro, Pau1 aBandinelli, Stefania1 aEriksson, Johan1 aBoomsma, Dorret, I1 aDehghan, Abbas1 aClarke, Robert1 aHamsten, Anders1 aBoerwinkle, Eric1 aJukema, Wouter1 aNaitza, Silvia1 aRidker, Paul, M1 aVölzke, Henry1 aDeary, Ian, J1 aReiner, Alexander, P1 aTrégouët, David-Alexandre1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aPeters, Annette1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/666703240nas a2200517 4500008004100000022001400041245009600055210006900151260001300220300000900233490000700242520182300249653000902072653002202081653002902103653003602132653003102168653001102199653002202210653003402232653001302266653001502279653001102294653001702305653004602322653001902368653000902387653003602396100001902432700001002451700001602461700001402477700001602491700001502507700001202522700001602534700001602550700001702566700001902583700001502602700001802617700001602635700001702651700001802668856003602686 2014 eng d a1096-002300aNovel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.0 aNovel gene variants predict serum levels of the cytokines IL18 a c2014 Jan a10-60 v653 aActivation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.
10aAged10aAged, 80 and over10aCalcium-Binding Proteins10aCARD Signaling Adaptor Proteins10aChromosomes, Human, Pair 210aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHaplotypes10aHumans10aInflammation10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1810aMale10aPolymorphism, Single Nucleotide1 aMatteini, A, M1 aLi, J1 aLange, E, M1 aTanaka, T1 aLange, L, A1 aTracy, R P1 aWang, Y1 aBiggs, M, L1 aArking, D E1 aFallin, M, D1 aChakravarti, A1 aPsaty, B M1 aBandinelli, S1 aFerrucci, L1 aReiner, A, P1 aWalston, J, D uhttps://chs-nhlbi.org/node/613304953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682004596nas a2201333 4500008004100000022001400041245010600055210006900161260001300230300001100243490000700254520134600261653001001607653002201617653000901639653001501648653004001663653001101703653003201714653003401746653001101780653000901791653001601800653003601816653001601852653001001868100001901878700001101897700001401908700001701922700002001939700001601959700001601975700001601991700001802007700001502025700001602040700001602056700001302072700001002085700001802095700001402113700002002127700001602147700001502163700001502178700001702193700001502210700001502225700001902240700001402259700001402273700001602287700001202303700001602315700001902331700001302350700001602363700001502379700001802394700001502412700001602427700001602443700001702459700001402476700001802490700001702508700001702525700001702542700001702559700001102576700001302587700001702600700002102617700001502638700001402653700002102667700001502688700001602703700001402719700001302733700001302746700001702759700001502776700001502791700001602806700001502822700001702837700001402854700002202868700001402890700001302904700001702917700001302934700001302947700001102960700001602971700001802987700001603005700001003021700001503031700001703046700001903063700001603082700001403098700001503112700001703127700001803144700001903162700001503181700001403196700001603210856003603226 2015 eng d a1476-557800aNovel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.0 aNovel loci associated with usual sleep duration the CHARGE Conso c2015 Oct a1232-90 v203 aUsual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
10aAdult10aAfrican Americans10aAged10aDyssomnias10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSelf Report10aSleep1 aGottlieb, D, J1 aHek, K1 aChen, T-H1 aWatson, N, F1 aEiriksdottir, G1 aByrne, E, M1 aCornelis, M1 aWarby, S, C1 aBandinelli, S1 aCherkas, L1 aEvans, D, S1 aGrabe, H, J1 aLahti, J1 aLi, M1 aLehtimäki, T1 aLumley, T1 aMarciante, K, D1 aPérusse, L1 aPsaty, B M1 aRobbins, J1 aTranah, G, J1 aVink, J, M1 aWilk, J, B1 aStafford, J, M1 aBellis, C1 aBiffar, R1 aBouchard, C1 aCade, B1 aCurhan, G C1 aEriksson, J, G1 aEwert, R1 aFerrucci, L1 aFülöp, T1 aGehrman, P, R1 aGoodloe, R1 aHarris, T B1 aHeath, A, C1 aHernandez, D1 aHofman, A1 aHottenga, J-J1 aHunter, D, J1 aJensen, M, K1 aJohnson, A D1 aKähönen, M1 aKao, L1 aKraft, P1 aLarkin, E, K1 aLauderdale, D, S1 aLuik, A, I1 aMedici, M1 aMontgomery, G, W1 aPalotie, A1 aPatel, S, R1 aPistis, G1 aPorcu, E1 aQuaye, L1 aRaitakari, O1 aRedline, S1 aRimm, E, B1 aRotter, J I1 aSmith, A V1 aSpector, T D1 aTeumer, A1 aUitterlinden, A G1 aVohl, M-C1 aWiden, E1 aWillemsen, G1 aYoung, T1 aZhang, X1 aLiu, Y1 aBlangero, J1 aBoomsma, D, I1 aGudnason, V1 aHu, F1 aMangino, M1 aMartin, N, G1 aO'Connor, G, T1 aStone, K, L1 aTanaka, T1 aViikari, J1 aGharib, S, A1 aPunjabi, N, M1 aRäikkönen, K1 aVölzke, H1 aMignot, E1 aTiemeier, H uhttps://chs-nhlbi.org/node/656603861nas a2200565 4500008004100000022001400041245010700055210006900162260001500231300001100246490000700257520230700264653001602571653000902587653001002596653001502606653001502621653002402636653001102660653003102671653001102702653001402713653001102727653001802738653002502756653000902781653003102790653002202821653003002843653001402873653003202887653002402919653003302943653001702976653001702993653001503010653001803025653001803043100001803061700001603079700002203095700001703117700002703134700002203161700001703183700001703200700002103217700002103238856003603259 2015 eng d a1555-905X00aNT-proBNP and troponin T and risk of rapid kidney function decline and incident CKD in elderly adults.0 aNTproBNP and troponin T and risk of rapid kidney function declin c2015 Feb 6 a205-140 v103 aBACKGROUND AND OBJECTIVES: Elevations in N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T are associated with poor cardiovascular outcomes. Whether elevations in these cardiac biomarkers are associated with decline in kidney function was evaluated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline in 3752 participants free of heart failure in the Cardiovascular Health Study. eGFR was determined from the Chronic Kidney Disease Epidemiology Collaboration equation using serum cystatin C. Rapid decline in kidney function was defined as decline in serum cystatin C eGFR≥30%, and incident CKD was defined as the onset of serum cystatin C eGFR<60 among those without CKD at baseline (n=2786). Cox regression models were used to examine the associations of each biomarker with kidney function decline adjusting for demographics, baseline serum cystatin C eGFR, diabetes, and other CKD risk factors.
RESULTS: In total, 503 participants had rapid decline in serum cystatin C eGFR over a mean follow-up time of 6.41 (1.81) years, and 685 participants developed incident CKD over a mean follow-up time of 6.41 (1.74) years. Participants in the highest quartile of N-terminal pro-B-type natriuretic peptide (>237 pg/ml) had an 67% higher risk of rapid decline and 38% higher adjusted risk of incident CKD compared with participants in the lowest quartile (adjusted hazard ratio for serum cystatin C eGFR rapid decline, 1.67; 95% confidence interval, 1.25 to 2.23; hazard ratio for incident CKD, 1.38; 95% confidence interval, 1.08 to 1.76). Participants in the highest category of troponin T (>10.58 pg/ml) had 80% greater risk of rapid decline compared with participants in the lowest category (adjusted hazard ratio, 1.80; 95% confidence interval, 1.35 to 2.40). The association of troponin T with incident CKD was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.92 to 1.50).
CONCLUSIONS: Elevated N-terminal pro-B-type natriuretic peptide and troponin T are associated with rapid decline of kidney function and incident CKD. Additional studies are needed to evaluate the mechanisms that may explain this association.
10aAge Factors10aAged10aAging10aBiomarkers10aCystatin C10aDisease Progression10aFemale10aGlomerular Filtration Rate10aHumans10aIncidence10aKidney10aLinear Models10aLongitudinal Studies10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aPrognosis10aProportional Hazards Models10aProspective Studies10aRenal Insufficiency, Chronic10aRisk Factors10aTime Factors10aTroponin T10aUnited States10aUp-Regulation1 aBansal, Nisha1 aKatz, Ronit1 aDalrymple, Lorien1 ade Boer, Ian1 aDeFilippi, Christopher1 aKestenbaum, Bryan1 aPark, Meyeon1 aSarnak, Mark1 aSeliger, Stephen1 aShlipak, Michael uhttps://chs-nhlbi.org/node/666105631nas a2200937 4500008004100000022001400041245013000055210006900185260001200254300001000266490000600276520305400282653000903336653001503345653002803360653001103388653001103399653000903410653001603419653003103435653002203466653002403488653002003512100001903532700002103551700001603572700002203588700001903610700002003629700001903649700001303668700002103681700002003702700002203722700001703744700001603761700001803777700002003795700001703815700001903832700002103851700001503872700001903887700002003906700001703926700002003943700002003963700002003983700002404003700002204027700001804049700001504067700002204082700002004104700002004124700002204144700003004166700001804196700002004214700002104234700001704255700001904272700001904291700002204310700002004332700002504352700002104377700002304398700001904421700002504440700002704465700001704492700001804509700002004527700002004547700002404567700001904591700001704610700003004627856003604657 2016 eng d a2213-859500aNatriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.0 aNatriuretic peptides and integrated risk assessment for cardiova c2016 10 a840-90 v43 aBACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.
METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.
FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure.
INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.
FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.
10aAged10aBiomarkers10aCardiovascular Diseases10aFemale10aHumans10aMale10aMiddle Aged10aNatriuretic Peptide, Brain10aPeptide Fragments10aProspective Studies10aRisk Assessment1 aWilleit, Peter1 aKaptoge, Stephen1 aWelsh, Paul1 aButterworth, Adam1 aChowdhury, Raj1 aSpackman, Sarah1 aPennells, Lisa1 aGao, Pei1 aBurgess, Stephen1 aFreitag, Daniel1 aSweeting, Michael1 aWood, Angela1 aCook, Nancy1 aJudd, Suzanne1 aTrompet, Stella1 aNambi, Vijay1 aOlsen, Michael1 aEverett, Brendan1 aKee, Frank1 aArnlöv, Johan1 aSalomaa, Veikko1 aLevy, Daniel1 aKauhanen, Jussi1 aLaukkanen, Jari1 aKavousi, Maryam1 aNinomiya, Toshiharu1 aCasas, Juan-Pablo1 aDaniels, Lori1 aLind, Lars1 aKistorp, Caroline1 aRosenberg, Jens1 aMueller, Thomas1 aRubattu, Speranza1 aPanagiotakos, Demosthenes1 aFranco, Oscar1 ade Lemos, James1 aLuchner, Andreas1 aKizer, Jorge1 aKiechl, Stefan1 aSalonen, Jukka1 aWannamethee, Goya1 ade Boer, Rudolf1 aNordestgaard, Børge1 aAndersson, Jonas1 aJørgensen, Torben1 aMelander, Olle1 aBallantyne, Christie1 aDeFilippi, Christopher1 aRidker, Paul1 aCushman, Mary1 aRosamond, Wayne1 aThompson, Simon1 aGudnason, Vilmundur1 aSattar, Naveed1 aDanesh, John1 aDi Angelantonio, Emanuele uhttps://chs-nhlbi.org/node/856702126nas a2200229 4500008004100000022001400041245014500055210006900200260001600269300001000285490000700295520138500302100001801687700001901705700002101724700002501745700002201770700002101792700002601813700002101839856003601860 2016 ENG d a1049-510X00aNeighborhood Characteristics are Associated with Racial and Gender Variation in Walking among Older Adults: the Cardiovascular Health Study.0 aNeighborhood Characteristics are Associated with Racial and Gend c2016 Jan 21 a17-260 v263 aOBJECTIVE: To examine variation by race and gender in the association between neighborhood socioeconomic status and walking among community-dwelling older adults.
DESIGN: Cross-sectional.
SETTING: Cardiovascular Health Study, a longitudinal population-based cohort.
PARTICIPANTS: 4,849 adults, aged > 65 years.
MEASUREMENTS: Participants reported the number of city blocks walked in the prior week. Neighborhood socioeconomic status (NSES) was measured at the level of the census tract. Negative binominal regression models were constructed to test the association between NSES and blocks walked. In the fully adjusted models, we included two-way and three-way interaction terms among race, gender, and NSES.
RESULTS: In adjusted analyses, among White residents in the lowest NSES quartile (most disadvantaged), men walked 64% more than women (P<.001), while in the highest NSES (most advantaged), men walked 43% more than women (P<.001). Among African American residents in the lowest NSES quartile, men walked 196% more blocks than women (P<.001).
CONCLUSIONS: Female gender is more strongly associated with walking for African Americans than for Whites in low SES neighborhoods but had a similar association with walking for both African Americans and Whites in high SES neighborhoods.
1 aYan, Tingjian1 aLiang, Li-Jung1 aVassar, Stefanie1 aKatz, Monica, Cheung1 aEscarce, José, J1 aLongstreth, W, T1 aMerkin, Sharon, Stein1 aBrown, Arleen, F uhttps://chs-nhlbi.org/node/700302328nas a2200229 4500008004100000022001400041245007500055210006900130260001600199300001200215490000800227520165300235100002101888700002001909700002501929700002001954700002101974700002101995700002302016700002302039856003602062 2016 eng d a1476-625600aNeighborhood Socioeconomic Status and Cognitive Function in Late Life.0 aNeighborhood Socioeconomic Status and Cognitive Function in Late c2016 Jun 15 a1088-970 v1833 aNeighborhood socioeconomic status (NSES) is associated with cognitive function, independently of individual demographic, health, and socioeconomic characteristics. However, research has been largely cross-sectional, and mechanisms of the association are unknown. In 1992-1993, Cardiovascular Health Study participants (n = 3,595; mean age = 74.8 years; 15.7% black) underwent cognitive testing and magnetic resonance imaging of white matter hyperintensities (WMH), and their addresses were geocoded. NSES was calculated using 1990 US Census data (block groups; 6 measures of wealth, education, and occupation). The Modified Mini-Mental State Examination (3MS) was used to assess general cognition, and the Digit Symbol Substitution Test (DSST) was used to assess speed of processing annually for 6 years. Associations of race-specific NSES tertiles with 3MS, DSST, and WMH were estimated using linear mixed-effects models accounting for geographic clustering, stratified by race, and adjusted for demographic, health, and individual socioeconomic status (education, income, lifetime occupational status) variables. In fully adjusted models, higher NSES was associated with higher 3MS scores in blacks (mean difference between highest and lowest NSES = 2.4 points; P = 0.004) and whites (mean difference = 0.7 points; P = 0.02) at baseline but not with changes in 3MS over time. NSES was marginally associated with DSST and was not associated with WMH. Adjustment for WMH did not attenuate NSES-3MS associations. Associations of NSES with cognition in late adulthood differ by race, are not explained by WMH, and are evident only at baseline.
1 aRosso, Andrea, L1 aFlatt, Jason, D1 aCarlson, Michelle, C1 aLovasi, Gina, S1 aRosano, Caterina1 aBrown, Arleen, F1 aMatthews, Karen, A1 aGianaros, Peter, J uhttps://chs-nhlbi.org/node/713206633nas a2201633 4500008004100000022001400041245008000055210006900135260001300204300001100217490000700228520260200235653002202837653002202859653003202881653003402913653001102947653003602958653001702994100001103011700002603022700001703048700001703065700001303082700001403095700001703109700001403126700001303140700001803153700001403171700001803185700002003203700002103223700001203244700001803256700001503274700001603289700002603305700001603331700001503347700001503362700001703377700001503394700001603409700001803425700001803443700001503461700001603476700001503492700001703507700001403524700001403538700001403552700001703566700002203583700001603605700001603621700001403637700002203651700001303673700001203686700001403698700001603712700001503728700001203743700001803755700001203773700001203785700001903797700001803816700001603834700001903850700001403869700001903883700001603902700001503918700001303933700001603946700002003962700001703982700001403999700001304013700001704026700001704043700001404060700001304074700001604087700001604103700001904119700001404138700001704152700002404169700001504193700001404208700001704222700001604239700002004255700001804275700001604293700001204309700001704321700001804338700001404356700002704370700001304397700001604410700001904426700001504445700001404460700001804474700001704492700001904509700001804528700002104546700001804567700002104585700001504606700001804621700001404639700001304653700001704666700001504683700002304698700001504721700001604736700001404752700001504766700001604781700002004797700001604817700002404833700001504857700001604872700001504888700002304903700001704926710002004943856003604963 2016 eng d a1476-557800aA novel Alzheimer disease locus located near the gene encoding tau protein.0 anovel Alzheimer disease locus located near the gene encoding tau c2016 Jan a108-170 v213 aAPOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
10aAlzheimer Disease10aApolipoprotein E410aChromosomes, Human, Pair 1710aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10atau Proteins1 aJun, G1 aIbrahim-Verbaas, C, A1 aVronskaya, M1 aLambert, J-C1 aChung, J1 aNaj, A, C1 aKunkle, B, W1 aWang, L-S1 aBis, J C1 aBellenguez, C1 aHarold, D1 aLunetta, K, L1 aDeStefano, A, L1 aGrenier-Boley, B1 aSims, R1 aBeecham, G, W1 aSmith, A V1 aChouraki, V1 aHamilton-Nelson, K, L1 aIkram, M, A1 aFiévet, N1 aDenning, N1 aMartin, E, R1 aSchmidt, H1 aKamatani, Y1 aDunstan, M, L1 aValladares, O1 aLaza, A, R1 aZelenika, D1 aRamirez, A1 aForoud, T, M1 aChoi, S-H1 aBoland, A1 aBecker, T1 aKukull, W, A1 avan der Lee, S, J1 aPasquier, F1 aCruchaga, C1 aBeekly, D1 aFitzpatrick, A, L1 aHanon, O1 aGill, M1 aBarber, R1 aGudnason, V1 aCampion, D1 aLove, S1 aBennett, D, A1 aAmin, N1 aBerr, C1 aTsolaki, Magda1 aBuxbaum, J, D1 aLopez, O, L1 aDeramecourt, V1 aFox, N, C1 aCantwell, L, B1 aTárraga, L1 aDufouil, C1 aHardy, J1 aCrane, P, K1 aEiriksdottir, G1 aHannequin, D1 aClarke, R1 aEvans, D1 aMosley, T, H1 aLetenneur, L1 aBrayne, C1 aMaier, W1 aDe Jager, P1 aEmilsson, V1 aDartigues, J-F1 aHampel, H1 aKamboh, M, I1 ade Bruijn, R, F A G1 aTzourio, C1 aPastor, P1 aLarson, E, B1 aRotter, J I1 aO'Donovan, M, C1 aMontine, T, J1 aNalls, M, A1 aMead, S1 aReiman, E, M1 aJonsson, P, V1 aHolmes, C1 aSt George-Hyslop, P, H1 aBoada, M1 aPassmore, P1 aWendland, J, R1 aSchmidt, R1 aMorgan, K1 aWinslow, A, R1 aPowell, J, F1 aCarasquillo, M1 aYounkin, S, G1 aJakobsdóttir, J1 aKauwe, J, S K1 aWilhelmsen, K, C1 aRujescu, D1 aNöthen, M, M1 aHofman, A1 aJones, L1 aHaines, J, L1 aPsaty, B M1 aVan Broeckhoven, C1 aHolmans, P1 aLauner, L J1 aMayeux, R1 aLathrop, M1 aGoate, A, M1 aEscott-Price, V1 aSeshadri, S1 aPericak-Vance, M, A1 aAmouyel, P1 aWilliams, J1 aDuijn, C M1 aSchellenberg, G, D1 aFarrer, L, A1 aIGAP Consortium uhttps://chs-nhlbi.org/node/668003468nas a2200541 4500008004100000022001400041245007100055210006900126260001300195300001000208490000600218520192500224100002302149700001702172700002602189700001602215700002602231700002002257700002302277700002502300700002202325700001802347700001902365700002002384700002202404700002202426700002002448700002402468700002202492700001402514700002002528700002402548700002502572700001602597700001902613700002802632700001602660700001902676700001902695700002402714700002202738700002102760700002302781700002002804700001802824710004802842856003602890 2016 eng d a1942-326800aNovel Genetic Loci Associated With Retinal Microvascular Diameter.0 aNovel Genetic Loci Associated With Retinal Microvascular Diamete c2016 Feb a45-540 v93 aBACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.
METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).
CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
1 aJensen, Richard, A1 aSim, Xueling1 aSmith, Albert, Vernon1 aLi, Xiaohui1 aJakobsdottir, Johanna1 aCheng, Ching-Yu1 aBrody, Jennifer, A1 aCotch, Mary, Frances1 aMcKnight, Barbara1 aKlein, Ronald1 aWang, Jie, Jin1 aKifley, Annette1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aKlein, Barbara, E K1 aRaffel, Leslie, J1 aLi, Xiang1 aIkram, Arfan, M1 aKlaver, Caroline, C1 avan der Lee, Sven, J1 aMutlu, Unal1 aHofman, Albert1 aUitterlinden, André, G1 aLiu, Chunyu1 aKraja, Aldi, T1 aMitchell, Paul1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWong, Tien, Y1 aCHARGE Exome Chip Blood Pressure Consortium uhttps://chs-nhlbi.org/node/690011779nas a2204225 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2016 eng d00a{Novel genetic loci underlying human intracranial volume identified through genome-wide association0 aNovel genetic loci underlying human intracranial volume identifi c12 a1569–15820 v193 aIntracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (Ïgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.1 aAdams, H., H.1 aHibar, D., P.1 aChouraki, V.1 aStein, J., L.1 aNyquist, P., A.1 aRenter?a, M., E.1 aTrompet, S.1 aArias-Vasquez, A.1 aSeshadri, S.1 aDesrivi?res, S.1 aBeecham, A., H.1 aJahanshad, N.1 aWittfeld, K.1 avan der Lee, S., J.1 aAbramovic, L.1 aAlhusaini, S.1 aAmin, N.1 aAndersson, M.1 aArfanakis, K.1 aAribisala, B., S.1 aArmstrong, N., J.1 aAthanasiu, L.1 aAxelsson, T.1 aBeiser, A.1 aBernard, M.1 aBis, J., C.1 aBlanken, L., M.1 aBlanton, S., H.1 aBohlken, M., M.1 aBoks, M., P.1 aBralten, J.1 aBrickman, A., M.1 aCarmichael, O.1 aChakravarty, M., M.1 aChauhan, G.1 aChen, Q.1 aChing, C., R.1 aCuellar-Partida, G.1 aBraber, A., D.1 aDoan, N., T.1 aEhrlich, S.1 aFilippi, I.1 aGe, T.1 aGiddaluru, S.1 aGoldman, A., L.1 aGottesman, R., F.1 aGreven, C., U.1 aGrimm, O.1 aGriswold, M., E.1 aGuadalupe, T.1 aHass, J.1 aHaukvik, U., K.1 aHilal, S.1 aHofer, E.1 aHoehn, D.1 aHolmes, A., J.1 aHoogman, M.1 aJanowitz, D.1 aJia, T.1 aKasperaviciute, D.1 aKim, S.1 aKlein, M.1 aKraemer, B.1 aLee, P., H.1 aLiao, J.1 aLiewald, D., C.1 aLopez, L., M.1 aLuciano, M.1 aMacare, C.1 aMarquand, A.1 aMatarin, M.1 aMather, K., A.1 aMattheisen, M.1 aMazoyer, B.1 aMcKay, D., R.1 aMcWhirter, R.1 aMilaneschi, Y.1 aMirza-Schreiber, N.1 aMuetzel, R., L.1 aManiega, S., M.1 aNho, K.1 aNugent, A., C.1 aLoohuis, L., M.1 aOosterlaan, J.1 aPapmeyer, M.1 aPappa, I.1 aPirpamer, L.1 aPudas, S.1 aP?tz, B.1 aRajan, K., B.1 aRamasamy, A.1 aRichards, J., S.1 aRisacher, S., L.1 aRoiz-Santia?ez, R.1 aRommelse, N.1 aRose, E., J.1 aRoyle, N., A.1 aRundek, T.1 aS?mann, P., G.1 aSatizabal, C., L.1 aSchmaal, L.1 aSchork, A., J.1 aShen, L.1 aShin, J.1 aShumskaya, E.1 aSmith, A., V.1 aSprooten, E.1 aStrike, L., T.1 aTeumer, A.1 aThomson, R.1 aTordesillas-Gutierrez, D.1 aToro, R.1 aTrabzuni, D.1 aVaidya, D.1 avan der Grond, J.1 avan der Meer, D.1 aVan Donkelaar, M., M.1 aVan Eijk, K., R.1 aVan Erp, T., G.1 avan Rooij, D.1 aWalton, E.1 aWestlye, L., T.1 aWhelan, C., D.1 aWindham, B., G.1 aWinkler, A., M.1 aWoldehawariat, G.1 aWolf, C.1 aWolfers, T.1 aXu, B.1 aYanek, L., R.1 aYang, J.1 aZijdenbos, A.1 aZwiers, M., P.1 aAgartz, I.1 aAggarwal, N., T.1 aAlmasy, L.1 aAmes, D.1 aAmouyel, P.1 aAndreassen, O., A.1 aArepalli, S.1 aAssareh, A., A.1 aBarral, S.1 aBastin, M., E.1 aBecker, D., M.1 aBecker, J., T.1 aBennett, D., A.1 aBlangero, J.1 avan Bokhoven, H.1 aBoomsma, D., I.1 aBrodaty, H.1 aBrouwer, R., M.1 aBrunner, H., G.1 aBuckner, R., L.1 aBuitelaar, J., K.1 aBulayeva, K., B.1 aCahn, W.1 aCalhoun, V., D.1 aCannon, D., M.1 aCavalleri, G., L.1 aChen, C.1 aCheng, C., Y.1 aCichon, S.1 aCookson, M., R.1 aCorvin, A.1 aCrespo-Facorro, B.1 aCurran, J., E.1 aCzisch, M.1 aDale, A., M.1 aDavies, G., E.1 aDe Geus, E., J.1 aDe Jager, P., L.1 ade Zubicaray, G., I.1 aDelanty, N.1 aDepondt, C.1 aDeStefano, A., L.1 aDillman, A.1 aDjurovic, S.1 aDonohoe, G.1 aDrevets, W., C.1 aDuggirala, R.1 aDyer, T., D.1 aErk, S.1 aEspeseth, T.1 aEvans, D., A.1 aFedko, I., O.1 aFern?ndez, G.1 aFerrucci, L.1 aFisher, S., E.1 aFleischman, D., A.1 aFord, I.1 aForoud, T., M.1 aFox, P., T.1 aFrancks, C.1 aFukunaga, M.1 aGibbs, J., R.1 aGlahn, D., C.1 aGollub, R., L.1 aG?ring, H., H.1 aGrabe, H., J.1 aGreen, R., C.1 aGruber, O.1 aGudnason, V.1 aGuelfi, S.1 aHansell, N., K.1 aHardy, J.1 aHartman, C., A.1 aHashimoto, R.1 aHegenscheid, K.1 aHeinz, A.1 aLe Hellard, S.1 aHernandez, D., G.1 aHeslenfeld, D., J.1 aHo, B., C.1 aHoekstra, P., J.1 aHoffmann, W.1 aHofman, A.1 aHolsboer, F.1 aHomuth, G.1 aHosten, N.1 aHottenga, J., J.1 aPol, H., E. Hulshof1 aIkeda, M.1 aIkram, M., K.1 aJack, C., R.1 aJenkinson, M.1 aJohnson, R.1 aJ?nsson, E., G.1 aJukema, J., W.1 aKahn, R., S.1 aKanai, R.1 aKloszewska, I.1 aKnopman, D., S.1 aKochunov, P.1 aKwok, J., B.1 aLawrie, S., M.1 aLema?tre, H.1 aLiu, X.1 aLongo, D., L.1 aLongstreth, W., T.1 aLopez, O., L.1 aLovestone, S.1 aMartinez, O.1 aMartinot, J., L.1 aMattay, V., S.1 aMcDonald, C.1 aMcIntosh, A., M.1 aMcMahon, K., L.1 aMcMahon, F., J.1 aMecocci, P.1 aMelle, I.1 aMeyer-Lindenberg, A.1 aMohnke, S.1 aMontgomery, G., W.1 aMorris, D., W.1 aMosley, T., H.1 aM?hleisen, T., W.1 aM?ller-Myhsok, B.1 aNalls, M., A.1 aNauck, M.1 aNichols, T., E.1 aNiessen, W., J.1 aN?then, M., M.1 aNyberg, L.1 aOhi, K.1 aOlvera, R., L.1 aOphoff, R., A.1 aPandolfo, M.1 aPaus, T.1 aPausova, Z.1 aPenninx, B., W.1 aPike, G., B.1 aPotkin, S., G.1 aPsaty, B., M.1 aReppermund, S.1 aRietschel, M.1 aRoffman, J., L.1 aRomanczuk-Seiferth, N.1 aRotter, J., I.1 aRyten, M.1 aSacco, R., L.1 aSachdev, P., S.1 aSaykin, A., J.1 aSchmidt, R.1 aSchofield, P., R.1 aSigurdsson, S.1 aSimmons, A.1 aSingleton, A.1 aSisodiya, S., M.1 aSmith, C.1 aSmoller, J., W.1 aSoininen, H.1 aSrikanth, V.1 aSteen, V., M.1 aStott, D., J.1 aSussmann, J., E.1 aThalamuthu, A.1 aTiemeier, H.1 aToga, A., W.1 aTraynor, B., J.1 aTroncoso, J.1 aTurner, J., A.1 aTzourio, C.1 aUitterlinden, A., G.1 aHern?ndez, M., C.1 aVan der Brug, M.1 avan der Lugt, A.1 aVan der Wee, N., J.1 avan Duijn, C., M.1 aVan Haren, N., E.1 aEnt, Van, T1 avan Tol, M., J.1 aVardarajan, B., N.1 aVeltman, D., J.1 aVernooij, M., W.1 aV?lzke, H.1 aWalter, H.1 aWardlaw, J., M.1 aWassink, T., H.1 aWeale, M., E.1 aWeinberger, D., R.1 aWeiner, M., W.1 aWen, W.1 aWestman, E.1 aWhite, T.1 aWong, T., Y.1 aWright, C., B.1 aZielke, H., R.1 aZonderman, A., B.1 aDeary, I., J.1 aDeCarli, C.1 aSchmidt, H.1 aMartin, N., G.1 aDe Craen, A., J.1 aWright, M., J.1 aLauner, L., J.1 aSchumann, G.1 aFornage, M.1 aFranke, B.1 aDebette, S.1 aMedland, S., E.1 aIkram, M., A.1 aThompson, P., M. uhttps://chs-nhlbi.org/node/856107019nas a2201849 4500008004100000022001400041245009300055210006900148260001300217490000700230520169900237100001901936700001901955700002101974700002301995700001602018700002502034700002202059700001802081700001902099700001702118700002602135700001602161700003002177700002302207700002102230700002502251700002002276700002102296700002302317700001602340700002302356700002002379700001702399700002102416700002302437700002202460700001402482700002502496700002902521700002402550700002102574700001802595700001702613700002502630700001802655700001802673700002002691700002202711700002502733700001302758700002002771700002402791700002502815700001902840700001902859700002102878700002702899700001902926700001402945700002402959700002302983700002203006700002503028700002603053700002303079700002203102700002103124700002003145700001803165700002603183700001703209700001803226700002303244700002403267700001203291700002103303700002103324700002203345700002103367700002703388700002303415700001803438700002203456700002003478700002403498700001803522700001903540700002103559700001603580700002003596700002303616700002003639700002203659700001603681700002103697700001903718700002203737700001703759700002003776700002303796700002703819700002403846700001903870700002203889700001903911700002403930700001503954700002003969700001903989700002204008700001904030700002104049700002204070700002304092700001904115700001904134700002104153700002504174700002004199700002004219700002204239700001604261700002004277700002204297700002004319700001604339700002604355700001904381700001504400700002404415700002304439700002604462700002404488700002504512700002104537700002304558700002104581700002404602700002104626700002504647700001704672700002704689700002004716700002004736700002304756700002304779700001804802700002504820700001704845700002904862700002404891700002404915710004304939710015104982856003605133 2017 eng d a1942-326800aNew Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.0 aNew Blood PressureAssociated Loci Identified in MetaAnalyses of c2017 Oct0 v103 aBACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.
METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.
CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
1 aKraja, Aldi, T1 aCook, James, P1 aWarren, Helen, R1 aSurendran, Praveen1 aLiu, Chunyu1 aEvangelou, Evangelos1 aManning, Alisa, K1 aGrarup, Niels1 aDrenos, Fotios1 aSim, Xueling1 aSmith, Albert, Vernon1 aAmin, Najaf1 aBlakemore, Alexandra, I F1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aFarmaki, Aliki-Eleni1 aFava, Cristiano1 aFerreira, Teresa1 aHerzig, Karl-Heinz1 aGiri, Ayush1 aGiulianini, Franco1 aGrove, Megan, L1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHave, Christian, T1 aHavulinna, Aki, S1 aZhang, He1 aJørgensen, Marit, E1 aKäräjämäki, AnneMari1 aKooperberg, Charles1 aLinneberg, Allan1 aLittle, Louis1 aLiu, Yongmei1 aBonnycastle, Lori, L1 aLu, Yingchang1 aMägi, Reedik1 aMahajan, Anubha1 aMalerba, Giovanni1 aMarioni, Riccardo, E1 aMei, Hao1 aMenni, Cristina1 aMorrison, Alanna, C1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRayner, Nigel, William1 aRiaz, Muhammad1 aRice, Ken1 aRichard, Melissa, A1 aSmith, Jennifer, A1 aSoutham, Lorraine1 aStančáková, Alena1 aStirrups, Kathleen, E1 aTragante, Vinicius1 aTuomi, Tiinamaija1 aTzoulaki, Ioanna1 aVarga, Tibor, V1 aWeiss, Stefan1 aYiorkas, Andrianos, M1 aYoung, Robin1 aZhang, Weihua1 aBarnes, Michael, R1 aCabrera, Claudia, P1 aGao, He1 aBoehnke, Michael1 aBoerwinkle, Eric1 aChambers, John, C1 aConnell, John, M1 aChristensen, Cramer, K1 ade Boer, Rudolf, A1 aDeary, Ian, J1 aDedoussis, George1 aDeloukas, Panos1 aDominiczak, Anna, F1 aDörr, Marcus1 aJoehanes, Roby1 aEdwards, Todd, L1 aEsko, Tõnu1 aFornage, Myriam1 aFranceschini, Nora1 aFranks, Paul, W1 aGambaro, Giovanni1 aGroop, Leif1 aHallmans, Göran1 aHansen, Torben1 aHayward, Caroline1 aHeikki, Oksa1 aIngelsson, Erik1 aTuomilehto, Jaakko1 aJarvelin, Marjo-Riitta1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, S1 aLakka, Timo, A1 aLangenberg, Claudia1 aLind, Lars1 aLoos, Ruth, J F1 aLaakso, Markku1 aMcCarthy, Mark, I1 aMelander, Olle1 aMohlke, Karen, L1 aMorris, Andrew, P1 aPalmer, Colin, N A1 aPedersen, Oluf1 aPolasek, Ozren1 aPoulter, Neil, R1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSever, Peter, J1 aSkaaby, Tea1 aStafford, Jeanette, M1 aStarr, John, M1 aHarst, Pim1 avan der Meer, Peter1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aGudnason, Vilmundur1 aWareham, Nicholas, J1 aWilson, James, G1 aWiller, Cristen, J1 aWitte, Daniel, R1 aZeggini, Eleftheria1 aSaleheen, Danish1 aButterworth, Adam, S1 aDanesh, John1 aAsselbergs, Folkert, W1 aWain, Louise, V1 aEhret, Georg, B1 aChasman, Daniel, I1 aCaulfield, Mark, J1 aElliott, Paul1 aLindgren, Cecilia, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aHowson, Joanna, M M1 aUnderstanding Society Scientific Group1 aCHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group† uhttps://chs-nhlbi.org/node/756909467nas a2203025 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2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749211478nas a2204105 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2017 eng d00a{Novel genetic loci associated with hippocampal volume0 aNovel genetic loci associated with hippocampal volume c01 a136240 v83 aThe hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.1 aHibar, D., P.1 aAdams, H., H. H.1 aJahanshad, N.1 aChauhan, G.1 aStein, J., L.1 aHofer, E.1 aRenteria, M., E.1 aBis, J., C.1 aArias-Vasquez, A.1 aIkram, M., K.1 aDesrivi?res, S.1 aVernooij, M., W.1 aAbramovic, L.1 aAlhusaini, S.1 aAmin, N.1 aAndersson, M.1 aArfanakis, K.1 aAribisala, B., S.1 aArmstrong, N., J.1 aAthanasiu, L.1 aAxelsson, T.1 aBeecham, A., H.1 aBeiser, A.1 aBernard, M.1 aBlanton, S., H.1 aBohlken, M., M.1 aBoks, M., P.1 aBralten, J.1 aBrickman, A., M.1 aCarmichael, O.1 aChakravarty, M., M.1 aChen, Q.1 aChing, C., R. K.1 aChouraki, V.1 aCuellar-Partida, G.1 aCrivello, F.1 aBraber, den1 aDoan, N., T.1 aEhrlich, S.1 aGiddaluru, S.1 aGoldman, A., L.1 aGottesman, R., F.1 aGrimm, O.1 aGriswold, M., E.1 aGuadalupe, T.1 aGutman, B., A.1 aHass, J.1 aHaukvik, U., K.1 aHoehn, D.1 aHolmes, A., J.1 aHoogman, M.1 aJanowitz, D.1 aJia, T.1 aJ?rgensen, K., N.1 aKarbalai, N.1 aKasperaviciute, D.1 aKim, S.1 aKlein, M.1 aKraemer, B.1 aLee, P., H.1 aLiewald, D., C. M.1 aLopez, L., M.1 aLuciano, M.1 aMacare, C.1 aMarquand, A., F.1 aMatarin, M.1 aMather, K., A.1 aMattheisen, M.1 aMcKay, D., R.1 aMilaneschi, Y.1 aManiega, Mu?oz1 aNho, K.1 aNugent, A., C.1 aNyquist, P.1 aLoohuis, L., M. O.1 aOosterlaan, J.1 aPapmeyer, M.1 aPirpamer, L.1 aP?tz, B.1 aRamasamy, A.1 aRichards, J., S.1 aRisacher, S., L.1 aRoiz-Santia?ez, R.1 aRommelse, N.1 aRopele, S.1 aRose, E., J.1 aRoyle, N., A.1 aRundek, T.1 aS?mann, P., G.1 aSaremi, A.1 aSatizabal, C., L.1 aSchmaal, L.1 aSchork, A., J.1 aShen, L.1 aShin, J.1 aShumskaya, E.1 aSmith, A., V.1 aSprooten, E.1 aStrike, L., T.1 aTeumer, A.1 aTordesillas-Gutierrez, D.1 aToro, R.1 aTrabzuni, D.1 aTrompet, S.1 aVaidya, D.1 avan der Grond, J.1 avan der Lee, S., J.1 avan der Meer, D.1 avan Donkelaar, M., M. J.1 aVan Eijk, K., R.1 avan Erp, T., G. M.1 avan Rooij, D.1 aWalton, E.1 aWestlye, L., T.1 aWhelan, C., D.1 aWindham, B., G.1 aWinkler, A., M.1 aWittfeld, K.1 aWoldehawariat, G.1 aWolf, C.1 aWolfers, T.1 aYanek, L., R.1 aYang, J.1 aZijdenbos, A.1 aZwiers, M., P.1 aAgartz, I.1 aAlmasy, L.1 aAmes, D.1 aAmouyel, P.1 aAndreassen, O., A.1 aArepalli, S.1 aAssareh, A., A.1 aBarral, S.1 aBastin, M., E.1 aBecker, D., M.1 aBecker, J., T.1 aBennett, D., A.1 aBlangero, J.1 avan Bokhoven, H.1 aBoomsma, D., I.1 aBrodaty, H.1 aBrouwer, R., M.1 aBrunner, H., G.1 aBuckner, R., L.1 aBuitelaar, J., K.1 aBulayeva, K., B.1 aCahn, W.1 aCalhoun, V., D.1 aCannon, D., M.1 aCavalleri, G., L.1 aCheng, C., Y.1 aCichon, S.1 aCookson, M., R.1 aCorvin, A.1 aCrespo-Facorro, B.1 aCurran, J., E.1 aCzisch, M.1 aDale, A., M.1 aDavies, G., E.1 ade Craen, A., J. M.1 ade Geus, E., J. C.1 aDe Jager, P., L.1 ade Zubicaray, G., I.1 aDeary, I., J.1 aDebette, S.1 aDeCarli, C.1 aDelanty, N.1 aDepondt, C.1 aDeStefano, A.1 aDillman, A.1 aDjurovic, S.1 aDonohoe, G.1 aDrevets, W., C.1 aDuggirala, R.1 aDyer, T., D.1 aEnzinger, C.1 aErk, S.1 aEspeseth, T.1 aFedko, I., O.1 aFern?ndez, G.1 aFerrucci, L.1 aFisher, S., E.1 aFleischman, D., A.1 aFord, I.1 aFornage, M.1 aForoud, T., M.1 aFox, P., T.1 aFrancks, C.1 aFukunaga, M.1 aGibbs, J., R.1 aGlahn, D., C.1 aGollub, R., L.1 aG?ring, H., H. H.1 aGreen, R., C.1 aGruber, O.1 aGudnason, V.1 aGuelfi, S.1 aH?berg, A., K.1 aHansell, N., K.1 aHardy, J.1 aHartman, C., A.1 aHashimoto, R.1 aHegenscheid, K.1 aHeinz, A.1 aLe Hellard, S.1 aHernandez, D., G.1 aHeslenfeld, D., J.1 aHo, B., C.1 aHoekstra, P., J.1 aHoffmann, W.1 aHofman, A.1 aHolsboer, F.1 aHomuth, G.1 aHosten, N.1 aHottenga, J., J.1 aHuentelman, M.1 aPol, H., E. Hulshof1 aIkeda, M.1 aJack, C., R.1 aJenkinson, M.1 aJohnson, R.1 aJ?nsson, E., G.1 aJukema, J., W.1 aKahn, R., S.1 aKanai, R.1 aKloszewska, I.1 aKnopman, D., S.1 aKochunov, P.1 aKwok, J., B.1 aLawrie, S., M.1 aLema?tre, H.1 aLiu, X.1 aLongo, D., L.1 aLopez, O., L.1 aLovestone, S.1 aMartinez, O.1 aMartinot, J., L.1 aMattay, V., S.1 aMcDonald, C.1 aMcIntosh, A., M.1 aMcMahon, F., J.1 aMcMahon, K., L.1 aMecocci, P.1 aMelle, I.1 aMeyer-Lindenberg, A.1 aMohnke, S.1 aMontgomery, G., W.1 aMorris, D., W.1 aMosley, T., H.1 aM?hleisen, T., W.1 aM?ller-Myhsok, B.1 aNalls, M., A.1 aNauck, M.1 aNichols, T., E.1 aNiessen, W., J.1 aN?then, M., M.1 aNyberg, L.1 aOhi, K.1 aOlvera, R., L.1 aOphoff, R., A.1 aPandolfo, M.1 aPaus, T.1 aPausova, Z.1 aPenninx, B., W. J. H.1 aPike, G., B.1 aPotkin, S., G.1 aPsaty, B., M.1 aReppermund, S.1 aRietschel, M.1 aRoffman, J., L.1 aRomanczuk-Seiferth, N.1 aRotter, J., I.1 aRyten, M.1 aSacco, R., L.1 aSachdev, P., S.1 aSaykin, A., J.1 aSchmidt, R.1 aSchmidt, H.1 aSchofield, P., R.1 aSigursson, S.1 aSimmons, A.1 aSingleton, A.1 aSisodiya, S., M.1 aSmith, C.1 aSmoller, J., W.1 aSoininen, H.1 aSteen, V., M.1 aStott, D., J.1 aSussmann, J., E.1 aThalamuthu, A.1 aToga, A., W.1 aTraynor, B., J.1 aTroncoso, J.1 aTsolaki, M.1 aTzourio, C.1 aUitterlinden, A., G.1 aHern?ndez, M., C. V.1 aVan der Brug, M.1 avan der Lugt, A.1 aVan der Wee, N., J. A.1 avan Haren, N., E. M.1 aEnt, van, 't1 avan Tol, M., J.1 aVardarajan, B., N.1 aVellas, B.1 aVeltman, D., J.1 aV?lzke, H.1 aWalter, H.1 aWardlaw, J., M.1 aWassink, T., H.1 aWeale, M., E.1 aWeinberger, D., R.1 aWeiner, M., W.1 aWen, W.1 aWestman, E.1 aWhite, T.1 aWong, T., Y.1 aWright, C., B.1 aZielke, R., H.1 aZonderman, A., B.1 aMartin, N., G.1 avan Duijn, C., M.1 aWright, M., J.1 aLongstreth, W., T.1 aSchumann, G.1 aGrabe, H., J.1 aFranke, B.1 aLauner, L., J.1 aMedland, S., E.1 aSeshadri, S.1 aThompson, P., M.1 aIkram, M., A. uhttps://chs-nhlbi.org/node/855202573nas a2200193 4500008004100000022001400041245009700055210006900152260001600221520196000237100002102197700001802218700001902236700002002255700002302275700002502298700002002323856003602343 2017 eng d a1933-287400aNovel polymorphisms associated with hyperalphalipoproteinemia and apparent cardioprotection.0 aNovel polymorphisms associated with hyperalphalipoproteinemia an c2017 Nov 213 aBACKGROUND: Hyperalphalipoproteinemia (HALP) is inversely correlated with coronary heart disease (CHD) although genetic variants associated with high serum levels of high-density lipoprotein cholesterol (HDL-C) have not been shown to be cardioprotective.
OBJECTIVE: The objective of the study was to uncover novel genetic variants associated with HALP and possibly with reduced risk of CHD.
METHODS: Exome sequencing data, HDL-C, and triglyceride levels were analyzed in 1645 subjects. They included the University of Maryland outpatients with high HDL-C (n = 12), Cardiovascular Health Study (n = 210), Jackson Heart Study (n = 402), Multi-Ethnic Study of Atherosclerosis (n = 404), Framingham Heart Study (n = 463), and Old Order Amish (n = 154).
RESULTS: Novel nonsynonymous single-nucleotide polymorphisms (nsSNPs) were identified in men and women with primary HALP (mean HDL-C, 145 ± 30 mg/dL). Using PolyPhen-2 and Combined Annotation Dependent Depletion to estimate the predictive effect of each nsSNP on the gene product, rare, deleterious polymorphisms in UGT1A3, PLLP, PLEKHH1, ANK2, DIS3L, ACACB, and LRP4 were identified in 16 subjects with HALP but not in any tested subject with low HDL-C (<40 mg/dL). In addition, a single novel polymorphism, rs376849274, was found in OSBPL1A. The majority of these candidate genes have been implicated in fat and lipid metabolism, and none of these subjects has a history of CHD despite 75% of subjects having risk factors for CHD. Overall, the probability of finding these nsSNPs in a non-high HDL-C population ranges from 1 × 10-17 to 1 × 10-25.
CONCLUSION: Novel functional polymorphisms in 8 candidate genes are associated with HALP in the absence of CHD. Future study is required to examine the extent to which these genes may affect HDL function and serve as potential therapeutic targets for CHD risk reduction.
1 aOates, Connor, P1 aKoenig, Darya1 aRhyne, Jeffrey1 aBogush, Nikolay1 aO'Connell, Jeffrey1 aMitchell, Braxton, D1 aMiller, Michael uhttps://chs-nhlbi.org/node/758011027nas a2203421 4500008004100000022001400041245014400055210006900199260000900268300001300277490000700290520159600297100002101893700001901914700002301933700001701956700002301973700001901996700001702015700002302032700002002055700001702075700002002092700002102112700002302133700001702156700002002173700002202193700002102215700002402236700002102260700002002281700002002301700002402321700002202345700002102367700002502388700002802413700002002441700002202461700002002483700002102503700002402524700002402548700001702572700002202589700001602611700002102627700002002648700001302668700001902681700001502700700001502715700002302730700002102753700001402774700001802788700002102806700002002827700002902847700002202876700002102898700002202919700001802941700001702959700001902976700002502995700001903020700001703039700002303056700001903079700002103098700001703119700002503136700002303161700002203184700002703206700002003233700002203253700001703275700001803292700002103310700001803331700001703349700001903366700001803385700001903403700001603422700001603438700001903454700001903473700001403492700002103506700002003527700002103547700001803568700001803586700002203604700002203626700002603648700002803674700002303702700002103725700001903746700002603765700002303791700002103814700001503835700002003850700001503870700002203885700001703907700002203924700002503946700002103971700002203992700002104014700002404035700002104059700002504080700001904105700001204124700002104136700001904157700001604176700001704192700002504209700002104234700002204255700001404277700002004291700002004311700001904331700002304350700002004373700001704393700002204410700002304432700002804455700001904483700002104502700002804523700001904551700002204570700001904592700002304611700002404634700002204658700002004680700001904700700001304719700001504732700001704747700001704764700001504781700001504796700001804811700002304829700002204852700002104874700002104895700001704916700002104933700002304954700001904977700002704996700002205023700002005045700002305065700002605088700001805114700002305132700002005155700002405175700001805199700002205217700002305239700001805262700001905280700002405299700002205323700002405345700002505369700001905394700002205413700002005435700001405455700002005469700001605489700002405505700002305529700002005552700001905572700002405591700002605615700002305641700001405664700002005678700001905698700002105717700002305738700002805761700002405789700002605813700001605839700001905855700001705874700002405891700001305915700001705928700001905945700001405964700002305978700002106001700002106022700002206043700002206065700001806087700001606105700002006121700002006141700002306161700002206184700002106206700002206227700002306249700002306272700001906295700002206314700002106336700001906357700002106376700001906397700002206416700002906438700002706467700002906494700002706523700001906550700002306569700002106592700002206613700001706635700001706652700001506669700002606684700002506710700001806735700001906753700003006772700001706802700001506819700002106834700002306855700002206878700002406900700002306924700002406947700001706971700002606988700002007014700002007034700002007054700002107074700001807095700002907113700002007142700002307162700002507185700002107210700001807231700002207249700002307271700001907294700002007313700002407333700001907357700001807376700002407394700001807418700002307436700002407459700002007483700002507503700001707528710002407545856003607569 2018 eng d a1932-620300aNovel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.0 aNovel genetic associations for blood pressure identified via gen c2018 ae01981660 v133 aHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aChasman, Daniel, I1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aBentley, Amy, R1 aBrown, Michael, R1 aSchwander, Karen1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aWojczynski, Mary, K1 aAlver, Maris1 aBoissel, Mathilde1 aCai, Qiuyin1 aCampbell, Archie1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLuan, Jian'an1 aMatoba, Nana1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRiaz, Muhammad1 aRueedi, Rico1 aRobino, Antonietta1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVitart, Veronique1 aWang, Yajuan1 aWare, Erin, B1 aWarren, Helen, R1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBoerwinkle, Eric1 aBorecki, Ingrid1 aBroeckel, Ulrich1 aBrown, Morris1 aBrumat, Marco1 aBurke, Gregory, L1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aCharumathi, Sabanayagam1 aChen, Yii-Der, Ida1 aConnell, John, M1 aCorrea, Adolfo1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDeng, Xuan1 aDing, Jingzhong1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEppinga, Ruben, N1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFelix, Stephan, B1 aForouhi, Nita, G1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGigante, Bruna1 aGu, Charles1 aGu, Dongfeng1 aHagenaars, Saskia, P1 aHallmans, Göran1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJohn, Ulrich1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLin, Shiow1 aLiu, Jianjun1 aLiu, Jingmin1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aNalls, Mike, A1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aNorris, Jill, M1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPerls, Thomas1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRoll, Kathryn1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRotter, Jerome, I1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aSchupf, Nicole1 aScott, William, R1 aSever, Peter, S1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVollenweider, Peter1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, Xing1 aBin Wei, Wen1 aWilliams, Christine1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLaakso, Markku1 aLaurie, Cathy, C1 aLeander, Karin1 aLehtimäki, Terho1 aStudy, Lifelines, Cohort1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPolasek, Ozren1 aPorteous, David, J1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aBouchard, Claude1 aChristensen, Kaare1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aGauderman, James1 aZhu, Xiaofeng1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aKooperberg, Charles1 aPalmas, Walter1 aRice, Kenneth1 aMorrison, Alanna, C1 aElliott, Paul1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aRao, Dabeeru, C1 aProvince, Michael, A1 aLevy, Daniel1 aInterAct Consortium uhttps://chs-nhlbi.org/node/779204114nas a2201297 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2019 eng d00a{New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders0 aNew alcoholrelated genes suggest shared genetic mechanisms with c09 a950–9610 v33 aExcessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.1 aEvangelou, E.1 aGao, H.1 aChu, C.1 aNtritsos, G.1 aBlakeley, P.1 aButts, A., R.1 aPazoki, R.1 aSuzuki, H.1 aKoskeridis, F.1 aYiorkas, A., M.1 aKaraman, I.1 aElliott, J.1 aLuo, Q.1 aAeschbacher, S.1 aBartz, T., M.1 aBaumeister, S., E.1 aBraund, P., S.1 aBrown, M., R.1 aBrody, J., A.1 aClarke, T., K.1 aDimou, N.1 aFaul, J., D.1 aHomuth, G.1 aJackson, A., U.1 aKentistou, K., A.1 aJoshi, P., K.1 aLemaitre, R., N.1 aLind, P., A.1 aLyytik?inen, L., P.1 aMangino, M.1 aMilaneschi, Y.1 aNelson, C., P.1 aNolte, I., M.1 aPer?l?, M., M.1 aPolasek, O.1 aPorteous, D.1 aRatliff, S., M.1 aSmith, J., A.1 aStan??kov?, A.1 aTeumer, A.1 aTuominen, S.1 aTh?riault, S.1 aVangipurapu, J.1 aWhitfield, J., B.1 aWood, A.1 aYao, J.1 aYu, B.1 aZhao, W.1 aArking, D., E.1 aAuvinen, J.1 aLiu, C.1 aM?nnikk?, M.1 aRisch, L.1 aRotter, J., I.1 aSnieder, H.1 aVeijola, J.1 aBlakemore, A., I.1 aBoehnke, M.1 aCampbell, H.1 aConen, D.1 aEriksson, J., G.1 aGrabe, H., J.1 aGuo, X.1 avan der Harst, P.1 aHartman, C., A.1 aHayward, C.1 aHeath, A., C.1 aJarvelin, M., R.1 aK?h?nen, M.1 aKardia, S., L. R.1 aK?hne, M.1 aKuusisto, J.1 aLaakso, M.1 aLahti, J.1 aLehtim?ki, T.1 aMcIntosh, A., M.1 aMohlke, K., L.1 aMorrison, A., C.1 aMartin, N., G.1 aOldehinkel, A., J.1 aPenninx, B., W. J. H.1 aPsaty, B., M.1 aRaitakari, O., T.1 aRudan, I.1 aSamani, N., J.1 aScott, L., J.1 aSpector, T., D.1 aVerweij, N.1 aWeir, D., R.1 aWilson, J., F.1 aLevy, D.1 aTzoulaki, I.1 aBell, J., D.1 aMatthews, P., M.1 aRothenfluh, A.1 aDesrivi?res, S.1 aSchumann, G.1 aElliott, P. uhttps://chs-nhlbi.org/node/851403191nas a2200373 4500008004100000022001400041245011600055210006900171260001200240300001300252490000700265520212000272653001002392653001602402653001102418653003402429653003102463653001102494653000902505653003702514653003302551653001602584653001402600653001602614100002202630700001802652700002002670700001802690700001802708700002102726700002202747700001202769856003602781 2019 eng d a1549-167600aNo causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study.0 aNo causal effects of serum urate levels on the risk of chronic k c2019 01 ae10027250 v163 aBACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).
METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.
CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.
10aAdult10aAge Factors10aFemale10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aMale10aMendelian Randomization Analysis10aRenal Insufficiency, Chronic10aSex Factors10aUric Acid10aYoung Adult1 aJordan, Daniel, M1 aChoi, Hyon, K1 aVerbanck, Marie1 aTopless, Ruth1 aWon, Hong-Hee1 aNadkarni, Girish1 aMerriman, Tony, R1 aDo, Ron uhttps://chs-nhlbi.org/node/804602786nas a2200289 4500008004100000022001400041245010600055210006900161260001600230300001200246490000600258520191000264100002202174700002202196700003002218700002402248700001902272700002002291700002302311700002202334700001902356700002202375700001702397700002302414700002302437856003602460 2019 eng d a2047-998000aNT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure.0 aNT pro BNP as a Mediator of the Racial Difference in Incident At c2019 Apr 02 ae0108680 v83 aBackground Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.
1 aWhitman, Isaac, R1 aVittinghoff, Eric1 adeFilippi, Christopher, R1 aGottdiener, John, S1 aAlonso, Alvaro1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aHoogeveen, Ron, C1 aArking, Dan, E1 aSelvin, Elizabeth1 aChen, Lin, Y1 aDewland, Thomas, A1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/800802520nas a2200181 4500008004100000022001400041245010500055210006900160260001600229520193100245100002402176700002102200700001802221700001902239700002002258700002402278856003602302 2020 eng d a1758-535X00aNon-Esterified Fatty Acids and Hospitalizations among Older Adults: The Cardiovascular Health Study.0 aNonEsterified Fatty Acids and Hospitalizations among Older Adult c2020 Sep 103 aBACKGROUND: We sought to determine associations between total serum concentrations of non-esterified fatty acids (NEFAs) and incident total and cause-specific hospitalizations in a community-living cohort of elders.
METHODS: We included 4715 participants in the Cardiovascular Health Study who had fasting total serum NEFA measured at the 1992/93 clinic visit and were followed for a median of 12 years. We identified all inpatient admissions requiring at least an overnight hospitalization and used primary diagnostic codes to categorize cause-specific hospitalizations. We used Cox proportional hazards regression models to determine associations with time-to-first hospitalization and Poisson regression for the rate ratios (RR) of hospitalizations and days hospitalized.
RESULTS: We identified 21339 hospitalizations during follow-up. In fully adjusted models, higher total NEFAs were significantly associated with higher risk of incident hospitalization (Hazard Ratio (HR) per SD [0.2 mEq/L]=1.07, 95%CI=1.03-1.10, P&0.001), number of hospitalizations (RR per SD=1.04, 95%CI=1.01-1.07, P=0.01), and total number of days hospitalized (RR per SD=1.06, 95%CI=1.01-1.10, P=0.01). Among hospitalization subtypes, higher NEFA was associated with higher likelihood of mental, neurologic, respiratory, and musculoskeletal causes of hospitalization. Among specific causes of hospitalization, higher NEFA was associated with diabetes, pneumonia, and gastrointestinal hemorrhage.
CONCLUSIONS: Higher fasting total serum NEFAs are associated with a broad array of causes of hospitalization among older adults. While some of these were expected, our results illustrate a possible utility of NEFAs as biomarkers for risk of hospitalization, and total days hospitalized, in older adults. Further research is needed to determine whether interventions based on NEFAs might be feasible.
1 aAhiawodzi, Peter, D1 aBůzková, Petra1 aDjoussé, Luc1 aIx, Joachim, H1 aKizer, Jorge, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/847603050nas a2200205 4500008004100000022001400041245013900055210006900194260001600263520237000279100002102649700001802670700001902688700002002707700002202727700001802749700001702767700002402784856003602808 2020 eng d a1532-541500aNon-Esterified Fatty Acids and Risks of Frailty, Disability, and Mobility Limitation in Older Adults: The Cardiovascular Health Study.0 aNonEsterified Fatty Acids and Risks of Frailty Disability and Mo c2020 Sep 223 aBACKGROUND/OBJECTIVES: Non-esterified fatty acids (NEFAs) play central roles in the relationship between adiposity and glucose metabolism, and they have been implicated in the pathogenesis of cardiovascular disease, but few studies have assessed their effects on complex geriatric syndromes like frailty that cross multiple organ systems. We sought to determine the relationships between NEFAs and incident frailty, disability, and mobility limitation in a population-based cohort of older persons.
METHODS: We analyzed 4,710 Cardiovascular Health Study (CHS) participants who underwent measurement of circulating total fasting NEFAs in 1992-1993 and were assessed for frailty in 1996-1997 and for disability and mobility limitation annually. We used ordinal logistic regression to model incident frailty, linear regression to model components of frailty, and Cox regression to model disability and mobility limitation in relation to baseline NEFAs. To ensure proportional hazards, we truncated follow-up at 9 years for disability and 6.5 years for mobility limitation.
RESULTS: A total of 42 participants became frail and 510 became pre-frail over a 4-year period, and we documented 1,720 cases of disability and 1,225 cases of mobility limitation during follow-up. NEFAs were positively associated in a dose-dependent manner with higher risks of incident frailty, disability, and mobility limitation. The adjusted odds ratios for frailty were 1.37 (95% confidence interval [CI] = 1.01-1.86; P = .04) across extreme tertiles and 1.17 (95% CI = 1.03-1.33; P = .01) per standard deviation increment. The corresponding hazard ratios for incident disability were 1.14 (95% CI = 1.01-1.30; P = .04) and 1.11 (95% CI = 1.06-1.17; P < .0001); those for incident mobility limitation were 1.23 (95% CI = 1.06-1.43; P = .006) and 1.15 (95% CI = 1.08-1.22; P < .0001). Results were largely consistent among both men and women. Among individual components of frailty, NEFAs were significantly associated with self-reported exhaustion (β = .07; standard error = .03; P = .02).
CONCLUSION: Circulating NEFAs are significantly associated with frailty, disability, and mobility limitation among older adults. These results highlight the broad spectrum of adverse health issues associated with NEFA in older adults.
1 aAhiawodzi, Peter1 aDjoussé, Luc1 aIx, Joachim, H1 aKizer, Jorge, R1 aTracy, Russell, P1 aArnold, Alice1 aNewman, Anne1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/847702690nas a2200205 4500008004100000022001400041245010100055210006900156260001300225300001100238490000600249520206300255100002102318700002802339700001802367700001902385700002002404700002402424856003602448 2020 eng d a2589-936800aNon-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study.0 aNonesterified fatty acids and telomere length in older adults Th c2020 Dec a1000580 v83 aBackground: Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults.
Material and methods: We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status.
Results: Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β = -0.034; SE = 0.015; = 0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error = 0.016; = 0.007); for comparison the coefficient for a single year of age in the same model was -0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β = -0.079; SE = 0.029; P = 0.01).
Conclusions: In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.
1 aAhiawodzi, Peter1 aFitzpatrick, Annette, L1 aDjoussé, Luc1 aIx, Joachim, H1 aKizer, Jorge, R1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/847802765nas a2200637 4500008004100000245014100041210006900182260000800251300001600259490000700275520106700282100001301349700002601362700001601388700001701404700001501421700002101436700001301457700002001470700001201490700001701502700001801519700001701537700001701554700001901571700001601590700001601606700002101622700001301643700002001656700001601676700002101692700001601713700001301729700001901742700002001761700002101781700002001802700001401822700001801836700001701854700001701871700001901888700001001907700001501917700002201932700001501954700002201969700001801991700001502009700002102024700001402045700002002059700001202079856003602091 2021 eng d00an-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies0 an3 Fatty Acid Biomarkers and Incident Type 2 Diabetes An Individ cMay a1133–11420 v443 a-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.\ For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.\ 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.\ Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.1 aQian, F.1 aKorat, A., V. Ardisso1 aImamura, F.1 aMarklund, M.1 aTintle, N.1 aVirtanen, J., K.1 aZhou, X.1 aBassett, J., K.1 aLai, H.1 aHirakawa, Y.1 aChien, K., L.1 aWood, A., C.1 aLankinen, M.1 aMurphy, R., A.1 aSamieri, C.1 aPertiwi, K.1 ade Mello, V., D.1 aGuan, W.1 aForouhi, N., G.1 aWareham, N.1 aHu, I., C. F. B.1 aRiserus, U.1 aLind, L.1 aHarris, W., S.1 aShadyab, A., H.1 aRobinson, J., G.1 aSteffen, L., M.1 aHodge, A.1 aGiles, G., G.1 aNinomiya, T.1 aUusitupa, M.1 aTuomilehto, J.1 am, J.1 aLaakso, M.1 aSiscovick, D., S.1 aHelmer, C.1 aGeleijnse, J., M.1 aWu, J., H. Y.1 aFretts, A.1 aLemaitre, R., N.1 aMicha, R.1 aMozaffarian, D.1 aSun, Q. uhttps://chs-nhlbi.org/node/945802649nas a2200265 4500008004100000022001400041245016700055210006900222260001600291300000700307490000700314520178800321100002502109700001902134700002402153700002202177700002002199700002002219700002302239700002202262700002002284700002002304700002302324856003602347 2021 eng d a1471-226100aNatural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA).0 aNatural killer cells gamma delta T cells and classical monocytes c2021 Jan 22 a450 v213 aBACKGROUND: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP).
METHODS: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level.
RESULTS: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14CD16) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 T helper cell subsets with average systolic blood pressure.
CONCLUSION: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.
1 aDelaney, Joseph, A C1 aOlson, Nels, C1 aSitlani, Colleen, M1 aFohner, Alison, E1 aHuber, Sally, A1 aLanday, Alan, L1 aHeckbert, Susan, R1 aTracy, Russell, P1 aPsaty, Bruce, M1 aFeinstein, Matt1 aDoyle, Margaret, F uhttps://chs-nhlbi.org/node/865802928nas a2200193 4500008004100000022001400041245012200055210006900177260001600246520228800262100002102550700001902571700001902590700002002609700002702629700001802656700002402674856003602698 2021 eng d a1523-683800aNonesterified Fatty Acids and Kidney Function Decline in Older Adults: Findings From the Cardiovascular Health Study.0 aNonesterified Fatty Acids and Kidney Function Decline in Older A c2021 Feb 033 aRATIONALE & OBJECTIVE: Circulating non-esterified fatty acids (NEFAs) make up a small portion of circulating lipids but are a metabolically important energy source. Excessive circulating NEFAs may contribute to lipotoxicity in many tissues, including the kidneys. We investigated the relationship between total circulating NEFA concentration and kidney outcomes in older, community-dwelling adults.
STUDY DESIGN: Prospective cohort study.
SETTING & PARTICIPANTS: 4,698 participants ≥65 years of age in the Cardiovascular Health Study who underwent total fasting serum NEFA concentration measurements in 1992-1993.
EXPOSURE: Fasting serum NEFA concentration at one timepoint.
OUTCOMES: Three primary outcomes: estimated glomerular filtration rate (eGFR) decline of >30%; the composite of eGFR decline ≥30% or kidney failure with replacement therapy (KFRT); and change in eGFR. These outcomes were assessed over 4- and 13-year periods.
ANALYTICAL APPROACH: Logistic regression for the dichotomous outcomes and mixed effects models for the continuous outcome, with sequential adjustment for baseline covariates. Inverse probability of attrition weighting was implemented to account for informative attrition during the follow-up periods.
RESULTS: Serum NEFA concentrations were not independently associated with kidney outcomes. In unadjusted and partially adjusted analyses, the highest quartile of serum NEFA concentration (compared to lowest) was associated with a higher risk of ≥30% eGFR decline at 4 years and faster rate of decline of eGFR. No associations were evident after adjustment for comorbidities, lipid levels, insulin sensitivity, medications, and vital signs: odds ratio 1.33 (95%CI 0.83-2.13); estimated glomerular filtration rate change per year, Q4 vs Q1: -0.15 ml/min/1.73m/year (95%CI -0.36 to 0.06).
LIMITATIONS: Single NEFA measurements, no measurements of post-glucose load NEFA concentrations or individual NEFA species, no measurement of baseline urine albumin.
CONCLUSIONS: A single fasting serum NEFA concentration was not independently associated with long-term adverse kidney outcomes in a cohort of older community-living adults.
1 aWalther, Carl, P1 aIx, Joachim, H1 aBiggs, Mary, L1 aKizer, Jorge, R1 aNavaneethan, Sankar, D1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/866815436nas a2205137 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2022 eng d a1546-171800aNew insights into the genetic etiology of Alzheimer's disease and related dementias.0 aNew insights into the genetic etiology of Alzheimers disease and c2022 Apr a412-4360 v543 aCharacterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
10aAlzheimer Disease10aCognitive Dysfunction10aGenome-Wide Association Study10aHumans10atau Proteins1 aBellenguez, Céline1 aKüçükali, Fahri1 aJansen, Iris, E1 aKleineidam, Luca1 aMoreno-Grau, Sonia1 aAmin, Najaf1 aNaj, Adam, C1 aCampos-Martin, Rafael1 aGrenier-Boley, Benjamin1 aAndrade, Victor1 aHolmans, Peter, A1 aBoland, Anne1 aDamotte, Vincent1 avan der Lee, Sven, J1 aCosta, Marcos, R1 aKuulasmaa, Teemu1 aYang, Qiong1 ade Rojas, Itziar1 aBis, Joshua, C1 aYaqub, Amber1 aProkic, Ivana1 aChapuis, Julien1 aAhmad, Shahzad1 aGiedraitis, Vilmantas1 aAarsland, Dag1 aGarcia-Gonzalez, Pablo1 aAbdelnour, Carla1 aAlarcón-Martín, Emilio1 aAlcolea, Daniel1 aAlegret, Montserrat1 aAlvarez, Ignacio1 aAlvarez, Victoria1 aArmstrong, Nicola, J1 aTsolaki, Anthoula1 aAntunez, Carmen1 aAppollonio, Ildebrando1 aArcaro, Marina1 aArchetti, Silvana1 aPastor, Alfonso, Arias1 aArosio, Beatrice1 aAthanasiu, Lavinia1 aBailly, Henri1 aBanaj, Nerisa1 aBaquero, Miquel1 aBarral, Sandra1 aBeiser, Alexa1 aPastor, Ana, Belén1 aBelow, Jennifer, E1 aBenchek, Penelope1 aBenussi, Luisa1 aBerr, Claudine1 aBesse, Céline1 aBessi, Valentina1 aBinetti, Giuliano1 aBizarro, Alessandra1 aBlesa, Rafael1 aBoada, Merce1 aBoerwinkle, Eric1 aBorroni, Barbara1 aBoschi, Silvia1 aBossù, Paola1 aBråthen, Geir1 aBressler, Jan1 aBresner, Catherine1 aBrodaty, Henry1 aBrookes, Keeley, J1 aBrusco, Luis, Ignacio1 aBuiza-Rueda, Dolores1 aBûrger, Katharina1 aBurholt, Vanessa1 aBush, William, S1 aCalero, Miguel1 aCantwell, Laura, B1 aChene, Geneviève1 aChung, Jaeyoon1 aCuccaro, Michael, L1 aCarracedo, Angel1 aCecchetti, Roberta1 aCervera-Carles, Laura1 aCharbonnier, Camille1 aChen, Hung-Hsin1 aChillotti, Caterina1 aCiccone, Simona1 aClaassen, Jurgen, A H R1 aClark, Christopher1 aConti, Elisa1 aCorma-Gómez, Anaïs1 aCostantini, Emanuele1 aCustodero, Carlo1 aDaian, Delphine1 aDalmasso, Maria, Carolina1 aDaniele, Antonio1 aDardiotis, Efthimios1 aDartigues, Jean-François1 ade Deyn, Peter, Paul1 aLopes, Katia, de Paiva1 ade Witte, Lot, D1 aDebette, Stephanie1 aDeckert, Jürgen1 aDel Ser, Teodoro1 aDenning, Nicola1 aDeStefano, Anita1 aDichgans, Martin1 aDiehl-Schmid, Janine1 aDiez-Fairen, Monica1 aRossi, Paolo, Dionigi1 aDjurovic, Srdjan1 aDuron, Emmanuelle1 aDüzel, Emrah1 aDufouil, Carole1 aEiriksdottir, Gudny1 aEngelborghs, Sebastiaan1 aEscott-Price, Valentina1 aEspinosa, Ana1 aEwers, Michael1 aFaber, Kelley, M1 aFabrizio, Tagliavini1 aNielsen, Sune, Fallgaard1 aFardo, David, W1 aFarotti, Lucia1 aFenoglio, Chiara1 aFernández-Fuertes, Marta1 aFerrari, Raffaele1 aFerreira, Catarina, B1 aFerri, Evelyn1 aFin, Bertrand1 aFischer, Peter1 aFladby, Tormod1 aFließbach, Klaus1 aFongang, Bernard1 aFornage, Myriam1 aFortea, Juan1 aForoud, Tatiana, M1 aFostinelli, Silvia1 aFox, Nick, C1 aFranco-Macías, Emlio1 aBullido, María, J1 aFrank-García, Ana1 aFroelich, Lutz1 aFulton-Howard, Brian1 aGalimberti, Daniela1 aGarcía-Alberca, Jose, Maria1 aGarcia-Gonzalez, Pablo1 aGarcia-Madrona, Sebastian1 aGarcia-Ribas, Guillermo1 aGhidoni, Roberta1 aGiegling, Ina1 aGiorgio, Giaccone1 aGoate, Alison, M1 aGoldhardt, Oliver1 aGomez-Fonseca, Duber1 aGonzález-Perez, Antonio1 aGraff, Caroline1 aGrande, Giulia1 aGreen, Emma1 aGrimmer, Timo1 aGrünblatt, Edna1 aGrunin, Michelle1 aGudnason, Vilmundur1 aGuetta-Baranes, Tamar1 aHaapasalo, Annakaisa1 aHadjigeorgiou, Georgios1 aHaines, Jonathan, L1 aHamilton-Nelson, Kara, L1 aHampel, Harald1 aHanon, Olivier1 aHardy, John1 aHartmann, Annette, M1 aHausner, Lucrezia1 aHarwood, Janet1 aHeilmann-Heimbach, Stefanie1 aHelisalmi, Seppo1 aHeneka, Michael, T1 aHernandez, Isabel1 aHerrmann, Martin, J1 aHoffmann, Per1 aHolmes, Clive1 aHolstege, Henne1 aVilas, Raquel, Huerto1 aHulsman, Marc1 aHumphrey, Jack1 aBiessels, Geert, Jan1 aJian, Xueqiu1 aJohansson, Charlotte1 aJun, Gyungah, R1 aKastumata, Yuriko1 aKauwe, John1 aKehoe, Patrick, G1 aKilander, Lena1 aStåhlbom, Anne, Kinhult1 aKivipelto, Miia1 aKoivisto, Anne1 aKornhuber, Johannes1 aKosmidis, Mary, H1 aKukull, Walter, A1 aKuksa, Pavel, P1 aKunkle, Brian, W1 aKuzma, Amanda, B1 aLage, Carmen1 aLaukka, Erika, J1 aLauner, Lenore1 aLauria, Alessandra1 aLee, Chien-Yueh1 aLehtisalo, Jenni1 aLerch, Ondrej1 aLleo, Alberto1 aLongstreth, William1 aLopez, Oscar1 ade Munain, Adolfo, Lopez1 aLove, Seth1 aLöwemark, Malin1 aLuckcuck, Lauren1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMacías, Juan1 aMacLeod, Catherine, A1 aMaier, Wolfgang1 aMangialasche, Francesca1 aSpallazzi, Marco1 aMarquié, Marta1 aMarshall, Rachel1 aMartin, Eden, R1 aMontes, Angel, Martín1 aRodríguez, Carmen, Martínez1 aMasullo, Carlo1 aMayeux, Richard1 aMead, Simon1 aMecocci, Patrizia1 aMedina, Miguel1 aMeggy, Alun1 aMehrabian, Shima1 aMendoza, Silvia1 aMenéndez-González, Manuel1 aMir, Pablo1 aMoebus, Susanne1 aMol, Merel1 aMolina-Porcel, Laura1 aMontrreal, Laura1 aMorelli, Laura1 aMoreno, Fermin1 aMorgan, Kevin1 aMosley, Thomas1 aNöthen, Markus, M1 aMuchnik, Carolina1 aMukherjee, Shubhabrata1 aNacmias, Benedetta1 aNgandu, Tiia1 aNicolas, Gaël1 aNordestgaard, Børge, G1 aOlaso, Robert1 aOrellana, Adelina1 aOrsini, Michela1 aOrtega, Gemma1 aPadovani, Alessandro1 aPaolo, Caffarra1 aPapenberg, Goran1 aParnetti, Lucilla1 aPasquier, Florence1 aPastor, Pau1 aPeloso, Gina1 aPérez-Cordón, Alba1 aPérez-Tur, Jordi1 aPericard, Pierre1 aPeters, Oliver1 aPijnenburg, Yolande, A L1 aPineda, Juan, A1 aPiñol-Ripoll, Gerard1 aPisanu, Claudia1 aPolak, Thomas1 aPopp, Julius1 aPosthuma, Danielle1 aPriller, Josef1 aPuerta, Raquel1 aQuenez, Olivier1 aQuintela, Inés1 aThomassen, Jesper, Qvist1 aRábano, Alberto1 aRainero, Innocenzo1 aRajabli, Farid1 aRamakers, Inez1 aReal, Luis, M1 aReinders, Marcel, J T1 aReitz, Christiane1 aReyes-Dumeyer, Dolly1 aRidge, Perry1 aRiedel-Heller, Steffi1 aRiederer, Peter1 aRoberto, Natalia1 aRodriguez-Rodriguez, Eloy1 aRongve, Arvid1 aAllende, Irene, Rosas1 aRosende-Roca, Maitée1 aRoyo, Jose, Luis1 aRubino, Elisa1 aRujescu, Dan1 aSáez, María, Eugenia1 aSakka, Paraskevi1 aSaltvedt, Ingvild1 aSanabria, Ángela1 aSánchez-Arjona, María, Bernal1 aSanchez-Garcia, Florentino1 aJuan, Pascual, Sánchez1 aSánchez-Valle, Raquel1 aSando, Sigrid, B1 aSarnowski, Chloe1 aSatizabal, Claudia, L1 aScamosci, Michela1 aScarmeas, Nikolaos1 aScarpini, Elio1 aScheltens, Philip1 aScherbaum, Norbert1 aScherer, Martin1 aSchmid, Matthias1 aSchneider, Anja1 aSchott, Jonathan, M1 aSelbæk, Geir1 aSeripa, Davide1 aSerrano, Manuel1 aSha, Jin1 aShadrin, Alexey, A1 aSkrobot, Olivia1 aSlifer, Susan1 aSnijders, Gijsje, J L1 aSoininen, Hilkka1 aSolfrizzi, Vincenzo1 aSolomon, Alina1 aSong, Yeunjoo1 aSorbi, Sandro1 aSotolongo-Grau, Oscar1 aSpalletta, Gianfranco1 aSpottke, Annika1 aSquassina, Alessio1 aStordal, Eystein1 aTartan, Juan, Pablo1 aTarraga, Lluis1 aTesí, Niccolo1 aThalamuthu, Anbupalam1 aThomas, Tegos1 aTosto, Giuseppe1 aTraykov, Latchezar1 aTremolizzo, Lucio1 aTybjærg-Hansen, Anne1 aUitterlinden, Andre1 aUllgren, Abbe1 aUlstein, Ingun1 aValero, Sergi1 aValladares, Otto1 aVan Broeckhoven, Christine1 aVance, Jeffery1 aVardarajan, Badri, N1 avan der Lugt, Aad1 aVan Dongen, Jasper1 avan Rooij, Jeroen1 avan Swieten, John1 aVandenberghe, Rik1 aVerhey, Frans1 aVidal, Jean-Sébastien1 aVogelgsang, Jonathan1 aVyhnalek, Martin1 aWagner, Michael1 aWallon, David1 aSan Wang, Li-1 aWang, Ruiqi1 aWeinhold, Leonie1 aWiltfang, Jens1 aWindle, Gill1 aWoods, Bob1 aYannakoulia, Mary1 aZare, Habil1 aZhao, Yi1 aZhang, Xiaoling1 aZhu, Congcong1 aZulaica, Miren1 aFarrer, Lindsay, A1 aPsaty, Bruce, M1 aGhanbari, Mohsen1 aRaj, Towfique1 aSachdev, Perminder1 aMather, Karen1 aJessen, Frank1 aIkram, Arfan, M1 ade Mendonça, Alexandre1 aHort, Jakub1 aTsolaki, Magda1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aWilliams, Julie1 aFrikke-Schmidt, Ruth1 aClarimon, Jordi1 aDeleuze, Jean-Francois1 aRossi, Giacomina1 aSeshadri, Sudha1 aAndreassen, Ole, A1 aIngelsson, Martin1 aHiltunen, Mikko1 aSleegers, Kristel1 aSchellenberg, Gerard, D1 aDuijn, Cornelia, M1 aSims, Rebecca1 avan der Flier, Wiesje, M1 aRuiz, Agustin1 aRamirez, Alfredo1 aLambert, Jean-Charles1 aEADB1 aGR@ACE1 aDEGESCO1 aEADI1 aGERAD1 aDemgene1 aFinnGen1 aADGC1 aCHARGE uhttps://chs-nhlbi.org/node/903502763nas a2200481 4500008004100000022001400041245012500055210006900180260001500249300000800264490000600272520128200278653003801560653003401598653001101632653002101643653003101664653003601695100002001731700002101751700002801772700002501800700002301825700001701848700001801865700002001883700001301903700001401916700001901930700002701949700002101976700002001997700002002017700002202037700002102059700002402080700002002104700001702124700001902141700001702160710006802177856003602245 2022 eng d a2399-364200aNon-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations.0 aNonlinear machine learning models incorporating SNPs and PRS imp c2022 08 22 a8560 v53 aPolygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMachine Learning10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aElgart, Michael1 aLyons, Genevieve1 aRomero-Brufau, Santiago1 aKurniansyah, Nuzulul1 aBrody, Jennifer, A1 aGuo, Xiuqing1 aLin, Henry, J1 aRaffield, Laura1 aGao, Yan1 aChen, Han1 ade Vries, Paul1 aLloyd-Jones, Donald, M1 aLange, Leslie, A1 aPeloso, Gina, M1 aFornage, Myriam1 aRotter, Jerome, I1 aRich, Stephen, S1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aLevy, Daniel1 aRedline, Susan1 aSofer, Tamar1 aNHLBI’s Trans-Omics in Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/916102505nas a2200277 4500008004100000022001400041245007600055210006900131260001600200300001100216490000700227520169000234100002001924700002101944700002001965700002101985700002002006700002502026700002102051700002302072700002802095700002002123700002502143700002302168856003602191 2023 eng d a1873-205400aNeighborhood greenspace and cognition: The cardiovascular health study.0 aNeighborhood greenspace and cognition The cardiovascular health c2023 Jan 03 a1029600 v793 aOBJECTIVES: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status.
METHODS: In a sample of non-demented older adults (n = 2141, average age = 75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant's residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated.
RESULTS: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95% CI = 0.50-0.99).
DISCUSSION: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.
1 aGodina, Sara, L1 aRosso, Andrea, L1 aHirsch, Jana, A1 aBesser, Lilah, M1 aLovasi, Gina, S1 aDonovan, Geoffrey, H1 aGarg, Parveen, K1 aPlatt, Jonathan, M1 aFitzpatrick, Annette, L1 aLopez, Oscar, L1 aCarlson, Michelle, C1 aMichael, Yvonne, L uhttps://chs-nhlbi.org/node/923802569nas a2200301 4500008004100000022001400041245012700055210006900182260001700251300001100268490000700279520165000286100002101936700002001957700002901977700002002006700002002026700002302046700001802069700002002087700002102107700002302128700001902151700002102170700002002191700002002211856003602231 2023 eng d a2352-872900aNeighborhood greenspace and neighborhood income associated with white matter grade worsening: Cardiovascular Health Study.0 aNeighborhood greenspace and neighborhood income associated with c2023 Oct-Dec ae124840 v153 aINTRODUCTION: We examined whether a combined measure of neighborhood greenspace and neighborhood median income was associated with white matter hyperintensity (WMH) and ventricle size changes.
METHODS: The sample included 1260 cognitively normal ≥ 65-year-olds with two magnetic resonance images (MRI; ≈ 5 years apart). WMH and ventricular size were graded from 0 (least) to 9 (most) abnormal (worsening = increase of ≥1 grade from initial to follow-up MRI scans). The four-category neighborhood greenspace-income measure was based on median neighborhood greenspace and income values at initial MRI. Multivariable logistic regression tested associations between neighborhood greenspace-income and MRI measures (worsening vs. not).
RESULTS: White matter grade worsening was more likely for those in lower greenspace-lower income neighborhoods than higher greenspace-higher income neighborhoods (odds ratio = 1.73; 95% confidence interval = 1.19-2.51).
DISCUSSION: The combination of lower neighborhood income and lower greenspace may be a risk factor for worsening white matter grade on MRI. However, findings need to be replicated in more diverse cohorts.
HIGHLIGHTS: Population-based cohort of older adults (≥ 65 years) with greenspace and MRI dataCombined measure of neighborhood greenspace and neighborhood income at initial MRIMRI outcomes included white matter hyperintensities (WMH) and ventricular sizeLongitudinal change in MRI outcomes measured approximately 5 years apartWorsening WMH over time more likely for lower greenspace-lower income neighborhoods.
1 aBesser, Lilah, M1 aLovasi, Gina, S1 aZambrano, Joyce, Jimenez1 aCamacho, Simone1 aDhanekula, Devi1 aMichael, Yvonne, L1 aGarg, Parveen1 aHirsch, Jana, A1 aSiscovick, David1 aHurvitz, Philip, M1 aBiggs, Mary, L1 aGalvin, James, E1 aBartz, Traci, M1 aLongstreth, W T uhttps://chs-nhlbi.org/node/953202581nas a2200229 4500008004100000022001400041245011900055210006900174260001600243520184500259100002102104700002602125700002302151700001902174700002002193700002202213700001702235700002102252700001802273700002402291856003602315 2023 eng d a1879-148400aNon-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study.0 aNonesterified fatty acids and risk of peripheral artery disease c2023 Jan 293 aBACKGROUND AND AIMS: Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons.
METHODS: We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992-1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998-1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI.
RESULTS: Mean age was 74.8 years, 59% were female, and 17% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95%CI = 1.06-2.13, p = 0.02) across extreme tertiles, and 1.14 (95%CI = 0.99-1.31, p = 0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95%CI = 0.69-1.32, p = 0.76) across extreme tertiles, and 1.03 (95%CI = 0.89-1.20, p = 0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up.
CONCLUSIONS: Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD.
1 aAhiawodzi, Peter1 aSolaru, Khendi, White1 aChaves, Paulo, H M1 aIx, Joachim, H1 aKizer, Jorge, R1 aTracy, Russell, P1 aNewman, Anne1 aSiscovick, David1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/9284