TY - JOUR T1 - Smoking and lung function in elderly men and women. The Cardiovascular Health Study. JF - JAMA Y1 - 1993 A1 - Higgins, M W A1 - Enright, P L A1 - Kronmal, R A A1 - Schenker, M B A1 - Anton-Culver, H A1 - Lyles, M KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Anthropometry KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Forced Expiratory Volume KW - Humans KW - Lung Diseases KW - Male KW - Prevalence KW - Prospective Studies KW - Reference Values KW - Respiratory Function Tests KW - Risk Factors KW - Smoking KW - United States KW - Vital Capacity AB -

OBJECTIVE: To investigate relationships between cigarette smoking and pulmonary function in elderly men and women.

DESIGN: Cross-sectional analysis of baseline data from a prospective, population-based study of risk factors, preclinical, and overt cardiovascular and pulmonary disease.

SETTING: Defined communities in Forsyth County, North Carolina; Pittsburgh, Pa; Sacramento County, California; and Washington County, Maryland.

POPULATION: A total of 5201 noninstitutionalized men and women 65 years of age and older.

MAIN OUTCOME MEASURES: Pulmonary function; means of forced expiratory volume in 1 second (FEV1) and forced vital capacity and prevalence of low FEV1 levels.

RESULTS: Prevalence of cigarette smoking was 10% to 20% and higher in women than men and in blacks than whites. Forced vital capacity and FEV1 levels were related positively to height and white race and negatively to age and waist girth. Age- and height-adjusted FEV1 means were 23% and 18% lower in male and female current smokers, respectively, than in never smokers but not reduced in never smokers currently living with a smoker. Smokers who quit before age 40 years had FEV1 levels similar to never smokers, but FEV1 levels were lower by 7% and 14% in smokers who quit at ages 40 to 60 years and older than 60 years, respectively. Lung function was related inversely to pack-years of cigarette use. Prevalence rates of impaired lung function were highest in current smokers and lowest in never smokers. Regression coefficients for the smoking variables were smaller in persons without cardiovascular or respiratory conditions than in the total cohort.

CONCLUSIONS: Cigarette smoking is associated with reduced pulmonary function in elderly men and women. However, smokers who quit, even after age 60 years, have better pulmonary function than continuing smokers.

VL - 269 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8492399?dopt=Abstract ER - TY - JOUR T1 - Black-white differences in subclinical cardiovascular disease among older adults: the Cardiovascular Health Study. CHS Collaborative Research Group. JF - J Clin Epidemiol Y1 - 1995 A1 - Manolio, T A A1 - Burke, G L A1 - Psaty, B M A1 - Newman, A B A1 - Haan, M A1 - Powe, N A1 - Tracy, R P A1 - O'Leary, D H KW - African Continental Ancestry Group KW - Aged KW - Cardiovascular Diseases KW - Carotid Arteries KW - European Continental Ancestry Group KW - Female KW - Geriatric Assessment KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Sex Factors AB -

Cardiovascular and all-cause mortality are higher in black than white Americans, but racial differences in clinical and subclinical cardiovascular disease (CVD) have not been examined in older adults. Clinical and subclinical CVD and its risk factors were compared in 4926 white and 244 black men and women aged 65 years and older. Black participants had lower socioeconomic status and generally higher prevalences of CVD and its risk factors, except for adverse lipid profiles. Common carotid wall thickness was greater in black than white women, and ankle-arm blood pressure ratios were lower in black women and men (p < 0.01). After adjustment for CVD risk factors, common carotid walls were significantly thicker and ankle-arm ratios were lower in blacks than whites of both sexes, while internal carotid walls were significantly thinner in black women. Racial differences in clinical and subclinical CVD in older adults are similar to those reported in younger populations and do not appear to be explained by CVD risk factors.

VL - 48 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7636516?dopt=Abstract ER - TY - JOUR T1 - Spirometry reference values for healthy elderly blacks. The Cardiovascular Health Study Research Group. JF - Chest Y1 - 1996 A1 - Enright, P L A1 - Arnold, A A1 - Manolio, T A A1 - Kuller, L H KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - European Continental Ancestry Group KW - Female KW - Forced Expiratory Volume KW - Humans KW - Male KW - Reference Values KW - Spirometry KW - United States KW - Vital Capacity AB -

Pulmonary function was assessed by spirometry in 497 black and 2,980 white ambulatory elderly male and female participants of the Cardiovascular Health Study. The quality assurance program prompted technicians to exceed American Thoracic Society recommendations for spirometry. A "healthy" subgroup of 235 black and 1,227 white participants age 65 years and older was identified by excluding current and former smoker, and those with self-reported asthma or emphysema, congestive heart failure, and poor-quality results of spirometry tests, since those factors were associated with a lower FEV1. Reference equations and normal ranges for elderly blacks for measurements of FEV1, FVC, and the FEV1/FVC ratio were then determined from the healthy group. These elderly blacks had an FVC about 6% lower than elderly whites, even after correcting for standing height, sitting height (trunk length), and age. The popular use of spirometry reference values from studies of middle-aged white subjects by applying a 12% race correction factor for black patients appears to overestimate predicted values.

VL - 110 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8989054?dopt=Abstract ER - TY - JOUR T1 - Does the association of risk factors and atherosclerosis change with age? An analysis of the combined ARIC and CHS cohorts. The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) investigators. JF - Stroke Y1 - 1997 A1 - Howard, G A1 - Manolio, T A A1 - Burke, G L A1 - Wolfson, S K A1 - O'Leary, D H KW - African Americans KW - African Continental Ancestry Group KW - Aged KW - Aging KW - Arteriosclerosis KW - Body Mass Index KW - Cardiovascular Physiological Phenomena KW - Cardiovascular System KW - Carotid Arteries KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Health Status KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Regression Analysis KW - Risk Factors KW - Sex Factors KW - Smoking KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

INTRODUCTION: A decrease in the estimated relative risk of cerebrovascular and cardiovascular diseases associated with known disease risk factors has been observed among elderly cohorts, perhaps suggesting that continued risk factor management in the elderly may not be as efficacious as with younger age groups. In this paper, the differential magnitude of the association of risk factors with atherosclerosis across the age spectrum from 45 years to older than 75 years is presented.

METHODS: Subclinical atherosclerosis as measured by carotid ultrasonography and risk factor prevalence were assessed using similar methods among participants aged 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study and among participants 65 years and older in the Cardiovascular Health Study (CHS). Pooling these two cohorts provided data on the relationship of risk factors and atherosclerosis on nearly 19,000 participants over a broad age range. Regression analyses were used to assess the consistency of the magnitude of the association of risk factors with atherosclerosis across the age spectrum separately for black and white participants in cross-sectional analyses.

RESULTS: As expected, each of the risk factors was globally (across all ages) associated with increased atherosclerosis. However, the magnitude of the association did not differ across the age spectrum for hypertension, low density lipoprotein cholesterol (LDL-c), fibrinogen, or body mass index (BMI). For whites, there was a significantly greater impact of smoking and HDL-C among older age strata but a smaller impact of diabetes. For black women, the impact of HDL-C decreased among the older age strata.

CONCLUSIONS: These data suggest that most risk factors continue to be associated with increased atherosclerosis at older ages, possibly suggesting a continued value in investigation of strategies to reduce atherosclerosis by controlling risk factors at older ages.

VL - 28 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9303011?dopt=Abstract ER - TY - JOUR T1 - Health status of individuals with mild stroke. JF - Stroke Y1 - 1997 A1 - Duncan, P W A1 - Samsa, G P A1 - Weinberger, M A1 - Goldstein, L B A1 - Bonito, A A1 - Witter, D M A1 - Enarson, C A1 - Matchar, D KW - Age Distribution KW - Aged KW - Cerebrovascular Disorders KW - European Continental Ancestry Group KW - Female KW - Health Status KW - Humans KW - Ischemic Attack, Transient KW - Male KW - Middle Aged KW - Social Support AB -

BACKGROUND AND PURPOSE: Diminished quality of life and limitations in higher levels of physical functioning are often underestimated in stroke and are not fully captured by measures such as the Barthel Index and the Rankin Outcome Scale. This study used additional measures to assess the health status of 304 persons with mild stroke and to compare these individuals with 184 persons with transient ischemic attack and 654 persons without history of stroke/transient ischemic attack but at elevated risk for stroke (asymptomatic group).

METHODS: Subjects were recruited from the Academic Medical Center Consortium (inpatients), the Cardiovascular Health Study (population-based sample of community-dwelling persons 65 years and older), and United HealthCare (inpatients and outpatients typically younger than 65 years). Subjects were interviewed by telephone or in person to assess activities of daily living (Barthel Index), depression (Center for Epidemiological Studies Depression Scale), health status (MOS-36), and utility for current health state.

RESULTS: Most respondents were independent on all Barthel items. The stroke group was more impaired on the MOS-36 than the asymptomatic group but similar to the group with transient ischemic attack. Health-related quality of life was lowest for persons with stroke. While symptom status and Barthel Index score were the strongest predictors of health status, the Barthel Index showed a consistent ceiling effect when compared with the physical function subscale of the MOS-36.

CONCLUSIONS: The consequences of even mild stroke affect all dimensions of health except pain. Standardized assessment of persons with stroke must evaluate across the entire continuum of health-related functions.

VL - 28 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9099189?dopt=Abstract ER - TY - JOUR T1 - Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1998 A1 - Kuller, L A1 - Fisher, L A1 - McClelland, R A1 - Fried, L A1 - Cushman, M A1 - Jackson, S A1 - Manolio, T KW - African Americans KW - Aged KW - Cardiovascular Physiological Phenomena KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Health Status KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Vascular Diseases AB -

A composite measure of subclinical vascular disease has been developed in the Cardiovascular Health Study (CHS). In previous reports, we measured the prevalence of subclinical disease among the original 5201 participants in the CHS, the relationship of risk factors to subclinical disease, and the association of subclinical disease to clinical coronary heart disease. In 1992 to 1993 (year 4 of the study), a larger cohort of 424 black women and 248 black men was added to the study. In this study, we have compared the prevalence of subclinical disease among blacks and whites in the CHS and the association with cardiovascular risk factors. The prevalence of subclinical disease for all participants (aged > or =65 years) was 41.3% for white women, 39.7% for black women, 41.9% for white men, and 43.7% for black men. The prevalence increased with age. The risk factor associations for subclinical disease were similar among blacks and whites. In multivariate analysis, age, systolic blood pressure, LDL cholesterol, smoking, and family history of myocardial infarction were independently associated with subclinical disease among both black and white women, while for white men, systolic blood pressure, use of antihypertensive medication, smoking, body mass index, and diastolic blood pressure (inverse) were related to subclinical disease. In black men, blood triglyceride level, use of antihypertensive medications, and family history of myocardial infarction (inverse) were associated with subclinical disease.

VL - 18 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9484995?dopt=Abstract ER - TY - JOUR T1 - Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study. JF - Stroke Y1 - 1998 A1 - Kuller, L H A1 - Shemanski, L A1 - Manolio, T A1 - Haan, M A1 - Fried, L A1 - Bryan, N A1 - Burke, G L A1 - Tracy, R A1 - Bhadelia, R KW - African Continental Ancestry Group KW - Aged KW - Apolipoproteins E KW - Brain KW - Cardiovascular Diseases KW - Cerebral Infarction KW - Cognition KW - Cognition Disorders KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Health Status KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Mental Status Schedule KW - Polymerase Chain Reaction KW - Risk Factors KW - Sex Factors KW - United States AB -

BACKGROUND AND PURPOSE: We determined the relationship between apolipoprotein (Apo)E, MRI, and low cognitive scores.

METHODS: The relationship between age, education, ApoE genotype, MRI examination of the brain, subclinical and clinical cardiovascular disease, and low (<80) score on the Modified Mini-Mental State Examination (3MSE, as modified by Teng and Chui) was evaluated for 3469 black and white participants in the Cardiovascular Health Study (CHS) in years 5 and 6 of the study. The participants were followed for up to 3 years.

RESULTS: The prevalence of scores <80 in years 5 and 6 of the CHS was 8.2% for participants without and 20.4% for those with prior history of stroke. Age, race, and education were important determinants of low 3MSE scores. The prevalence of ApoE-4 (odds ratio [OR], 1.6 [1.1 to 2.1]) was directly related to scores <80, as was high ventricular volume (OR, 1.6 [1.2 to 2.3]), high white matter grade (OR, 1.4 [1.1 to 1.9]), and infarctlike lesions (OR, 1.6 [1.2 to 2.1]) on the MRI in the multivariate analysis. A five-point or greater decline in scores over up to 3 years was more often observed for participants with low 3MSE scores at year 5, at older ages, with lower education, and experiencing incident stroke (OR, 3.6 [1.2 to 10.6]), ApoE-4 genotype (OR, 1.8 [1.4 to 2.3]), and with MRI findings of high ventricular volume (OR, 2.0 [1.5 to 2.7]), and infarctlike lesions (OR, 1.2 [0.9 to 1.5]).

CONCLUSIONS: These results demonstrate that vascular changes on MRI, measures of brain atrophy, ApoE-4, and age, education, and race are associated with low cognitive scores among older individuals. The MRI of the brain provides valuable information related to cognitive tests and decline over time. The potential exists for using MRI measurements to identify high-risk individuals for dementia and to test potential interventions to reduce the risk of dementia.

VL - 29 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9472879?dopt=Abstract ER - TY - JOUR T1 - Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Sakkinen, P A A1 - Cushman, M A1 - Psaty, B M A1 - Rodriguez, B A1 - Boineau, R A1 - Kuller, L H A1 - Tracy, R P KW - Aged KW - Aged, 80 and over KW - alpha-2-Antiplasmin KW - Antifibrinolytic Agents KW - Asian Continental Ancestry Group KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Fibrinolysin KW - Fibrinolysis KW - Humans KW - Insulin Resistance KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Plasminogen Activator Inhibitor 1 KW - Risk Factors AB -

Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073949?dopt=Abstract ER - TY - JOUR T1 - Race- and sex-specific ECG models for left ventricular mass in older populations. Factors influencing overestimation of left ventricular hypertrophy prevalence by ECG criteria in African-Americans. JF - J Electrocardiol Y1 - 2000 A1 - Rautaharju, P M A1 - Park, L P A1 - Gottdiener, J S A1 - Siscovick, D A1 - Boineau, R A1 - Smith, V A1 - Powe, N R KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Anthropometry KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Predictive Value of Tests KW - Prevalence KW - Sex Factors KW - Ultrasonography AB -

The validity of the reported high prevalence of left ventricular hypertrophy (LVH) among African-American men and women has been questioned owing to conflicting echocardiographic evidence. We used echocardiographic left ventricular mass (LVM) from M-mode measurements to evaluate associations between LVM, body size, and electrocardiographic (ECG) variables in 3,627 white and African-American men and women 65 years of age and older who were participants of the Cardiovascular Health Study (CHS), a multicenter cohort study of risk factors for coronary heart disease and stroke. ECG amplitudes used in LVH criteria were substantially higher in African-Americans, with apparent LVH prevalence 2 to 3 times higher in African American men and women than in white men and women, although there was no significant racial difference in echocardiographic LVM. The higher apparent LVH prevalence by Sokolow-Lyon criteria in African-American men is in part owing to smaller lateral chest diameter. In women, reasons for racial differences in ECG LVH prevalence remain largely unexplained although a small part of the excess LVH in African-American women by the Sokolow-Lyon criteria appears to be owing to a larger lateral chest semidiameter in white women. ECG variables alone were too inaccurate for LVM prediction, and it was necessary to incorporate in all ECG models body weight that was properly adjusted for race and sex. This resulted in modest LVM prediction accuracy, with R-square values ranging from .22 to .36. Race- and sex-specific ECG models introduced for LVM estimation with an appropriate adjustment for body size differences are expected to facilitate evaluation of LVH status in contrasting racial population groups.

VL - 33 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10954373?dopt=Abstract ER - TY - JOUR T1 - Tobacco, hypertension, and vascular disease: risk factors for renal functional decline in an older population. JF - Kidney Int Y1 - 2000 A1 - Bleyer, A J A1 - Shemanski, L R A1 - Burke, G L A1 - Hansen, K J A1 - Appel, R G KW - African Continental Ancestry Group KW - Aged KW - Aging KW - Cohort Studies KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Kidney KW - Male KW - Regression Analysis KW - Retrospective Studies KW - Risk Factors KW - Smoking KW - Vascular Diseases AB -

BACKGROUND: A decline in renal function with age has been noted in some but not all individuals. The purpose of this study was to identify risk factors associated with a clinically significant increase in serum creatinine (of at least 0.3 mg/dL) in an older nondiabetic population.

METHODS: A retrospective case-control study was performed analyzing data obtained from 4142 nondiabetic participants of the Cardiovascular Health Study Cohort, all at least 65 years of age, who had two measurements of serum creatinine performed at least three years apart. Cases were identified as participants who developed an increase in serum creatinine of at least 0.3 mg/dL, with controls including participants who did not sustain such an increase.

RESULTS: There was an increase in the serum creatinine of at least 0.3 mg/dL in 2.8% of the population. In a multivariate "best-fit" model adjusted for gender, weight, black race, baseline serum creatinine, and age, the following factors were associated with an increase in serum creatinine: number of cigarettes smoked per day, systolic blood pressure, and maximum internal carotid artery intimal thickness.

CONCLUSIONS: These data suggest that three very preventable or treatable conditions-hypertension, smoking, and prevalent vascular disease, which are associated with large and small vessel disease-are highly associated with clinically important changes in renal function in an older population.

VL - 57 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10792626?dopt=Abstract ER - TY - JOUR T1 - Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events. JF - Am J Hypertens Y1 - 2002 A1 - Hindorff, Lucia A A1 - Heckbert, Susan R A1 - Tracy, Russell A1 - Tang, Zhonghua A1 - Psaty, Bruce M A1 - Edwards, Karen L A1 - Siscovick, David S A1 - Kronmal, Richard A A1 - Nazar-Stewart, Valle KW - African Continental Ancestry Group KW - Aged KW - Blood Pressure KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Humans KW - Hypertension KW - Male KW - Polymorphism, Genetic KW - Receptor, Angiotensin, Type 1 KW - Receptors, Angiotensin KW - United States AB -

BACKGROUND: The angiotensin II type 1 receptor A1166C polymorphism has been associated with increased risks of hypertension and myocardial infarction in several small studies. We examined the association between this polymorphism and new-onset hypertension, blood pressure (BP) control, and incident cardiovascular events in a large population-based cohort of older adults.

METHODS: Eight hundred self-identified African Americans and 1,371 randomly selected white participants in the Cardiovascular Health Study were genotyped. The median duration of follow-up was 8.1 years.

RESULTS: The A1166C polymorphism was not associated with new-onset hypertension, with BP control, or with incident cardiovascular events in the overall population. In white participants, the CC genotype was associated with higher baseline systolic BP and pulse pressure, compared to the AC or AA genotype. In whites with treated hypertension at baseline, compared to the AA genotype, the CC genotype was associated with increased risks of incident congestive heart failure (hazard ratio = 2.5, 95% confidence interval [CI] 1.3-4.9) and incident ischemic stroke (hazard ratio = 2.6, 95% CI 1.1-6.0). These associations were not observed among white participants without treated hypertension, but the interaction of genotype with treated hypertension on ischemic stroke and heart failure was only marginally significant.

CONCLUSIONS: On the whole, in this large cohort of older adults, the A1166C polymorphism was not associated with BP control or incident cardiovascular events. The subgroup findings in treated hypertensives need to be confirmed in additional studies.

VL - 15 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12460700?dopt=Abstract ER - TY - JOUR T1 - Left atrial dimensions determined by M-mode echocardiography in black and white older (> or =65 years) adults (The Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2002 A1 - Manolio, Teri A A1 - Gottdiener, John S A1 - Tsang, Teresa S M A1 - Gardin, Julius M KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Blood Flow Velocity KW - Body Weight KW - Cardiovascular Diseases KW - Echocardiography KW - Electrocardiography KW - European Continental Ancestry Group KW - Evidence-Based Medicine KW - Female KW - Heart Atria KW - Heart Ventricles KW - Humans KW - Male KW - Multivariate Analysis KW - Prospective Studies KW - Risk Factors KW - Statistics as Topic KW - Ventricular Function, Left AB -

Stroke and atrial fibrillation are common and serious illnesses in the elderly, the risks of which are substantially increased by left atrial (LA) enlargement. Despite growing recognition of the importance of LA enlargement, the distribution and correlates of LA dimension in the elderly have not been well defined. A total of 3,882 women and men aged >65 years were studied. Increased LA dimension was independently associated with increased weight, mitral annular calcium, regional wall motion abnormalities, mitral early peak inflow velocity, and left ventricular (LV) fractional shortening. Increased LA dimension was negatively associated with aortic leaflet thickening. The relation with LV fractional shortening was curvilinear with a nadir at 35% to 40%. LA dimension in black men was approximately 1.9 mm less than in white men in multivariate analyses. Adjustment for spirometric lung volumes and chest dimensions appeared to diminish the race-LA dimension relation. Thus, LA dimension is strongly associated with weight and with several echocardiographic valvular abnormalities; its relation with LV fractional shortening is U-shaped with a nadir at the borderline of LV functional impairment.

VL - 90 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12398966?dopt=Abstract ER - TY - JOUR T1 - Prospective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism. JF - Am J Hematol Y1 - 2002 A1 - Folsom, Aaron R A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Heckbert, Susan R A1 - Aleksic, Nena KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Case-Control Studies KW - European Continental Ancestry Group KW - Genotype KW - Humans KW - Incidence KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Prothrombin KW - Recurrence KW - Research Design KW - Risk Factors KW - Thromboembolism KW - United States AB -

Case-control studies have indicated increased risk of venous thrombosis associated with the prothrombin gene G20210A polymorphism and with elevated plasma prothrombin levels. We sought to confirm these results in a prospective population-based study of 21,690 persons. We measured G20210A and prothrombin antigen on pre-event blood samples of 302 participants who developed venous thromboembolism (VTE) and 626 participants who remained free of VTE. Approximately 4.0% of cases and 2.4% of controls carried the G20210A polymorphism, but only one of 137 African Americans did. The odds ratio in whites was 1.87 (95% CI = 0.85, 4.11)--higher for those who reported a prior history of VTE (OR = 5.44) than those reporting no VTE history (OR = 1.41) and in those with idiopathic VTE (OR = 2.51) than those with secondary VTE (OR = 1.38). There was no association between venous thromboembolism and plasma prothrombin antigen level. We estimated that the G20210A polymorphism may account for approximately 2.5% of venous thromboembolism events in United States whites.

VL - 71 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12447958?dopt=Abstract ER - TY - JOUR T1 - Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. JF - Circulation Y1 - 2003 A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Edwards, Karen L A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Tang, Zhonghua A1 - Durda, J Peter A1 - Kronmal, Richard A A1 - Tracy, Russell P KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Brain Ischemia KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - European Continental Ancestry Group KW - Follow-Up Studies KW - Gene Frequency KW - Humans KW - Incidence KW - Linkage Disequilibrium KW - Polymorphism, Genetic KW - Receptors, Adrenergic, beta-2 KW - Risk Assessment KW - Stroke KW - United States AB -

BACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.

METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.

CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.

VL - 107 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12682000?dopt=Abstract ER - TY - JOUR T1 - Early age-related maculopathy in the cardiovascular health study. JF - Ophthalmology Y1 - 2003 A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Marino, Emily K A1 - Kuller, Lewis H A1 - Furberg, Curt A1 - Burke, Gregory L A1 - Hubbard, Larry D KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Blood Pressure KW - C-Reactive Protein KW - California KW - Cohort Studies KW - Diet KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Leukocyte Count KW - Longitudinal Studies KW - Macular Degeneration KW - Male KW - Mid-Atlantic Region KW - North Carolina KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Serum Albumin AB -

OBJECTIVE: To describe the prevalence of early age-related maculopathy (ARM) and its relation to atherosclerosis, lipids, hypertension, and inflammatory factors in a population studied for cardiovascular disease risk factors and outcomes.

DESIGN: Population-based cohort study.

PARTICIPANTS: A biracial population of 2361 adults (ranging from 69-97 years of age; 1998 whites and 363 blacks) living in four US counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were examined during the interval from 1997 to 1998.

METHODS: Drusen and other lesions typical of ARM were identified by examining a 45 degrees color fundus photograph of one eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System.

MAIN OUTCOME MEASURES: Early ARM.

RESULTS: Early ARM was present in 15.5% and late ARM in 1.3% of the cohort. The overall prevalence of any ARM was lower in blacks (9.1%) compared with whites (18.2%). While controlling for age, race, gender, and total calories consumed in the diet, factors associated with ARM were cerebral white matter disease as detected by magnetic resonance imaging (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.05, 2.16, P = 0.027), and lower serum total cholesterol (OR, per 10 mg/dl increase 0.95; 95% CI, 0.91, 0.98, P = 0.02). There were no associations between hypertension, blood pressure, common carotid artery plaque, or any systemic inflammatory factors studied and early ARM.

CONCLUSIONS: This population-based study documents the higher prevalence of ARM in whites compared with blacks. Although an association was found between signs of white matter disease and early ARM, there was no evidence of an association of ARM with either hypertension or inflammatory factors.

VL - 110 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12511342?dopt=Abstract ER - TY - JOUR T1 - Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. JF - J Thromb Haemost Y1 - 2003 A1 - Crainich, P A1 - Jenny, N S A1 - Tang, Z A1 - Arnold, A M A1 - Kuller, L H A1 - Manolio, T A1 - Sharrett, A R A1 - Tracy, R P KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Homozygote KW - Humans KW - Male KW - Myocardial Infarction KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Genetic KW - Promoter Regions, Genetic KW - Risk AB -

Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.

VL - 1 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12911596?dopt=Abstract ER - TY - JOUR T1 - Regional and racial differences in the prevalence of physician-diagnosed essential tremor in the United States. JF - Mov Disord Y1 - 2003 A1 - Louis, Elan D A1 - Fried, Linda P A1 - Fitzpatrick, Annette L A1 - Longstreth, William T A1 - Newman, Anne B KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Essential Tremor KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Physicians KW - Prevalence KW - United States AB -

For reasons that are unclear, prevalence estimates of essential tremor (ET) differ considerably across the United States. Separate communities have never been sampled within the framework of the same study to substantiate these differences. We estimated the prevalence of physician-diagnosed ET in the elderly in four communities in the United States in whom the same screening questions were used, and examined whether this prevalence differed between Caucasians and African Americans. The Cardiovascular Health Study recruited a sample of Medicare beneficiaries >/=65 years of age from four communities in different regions of the United States. In 1998 to 1999, 3,494 participants (mean age, 80.0 years; range, 70-103 years) answered a 12-question screen for ET, including the question, "has a doctor diagnosed you as having familial tremor or benign essential tremor?" Fifty-four participants reported that a doctor had diagnosed them as having ET (1.5%; 95% confidence interval, [CI], 1.1-2.0%). Prevalence was similar across the four communities (1.1-2.0%). A larger proportion of Caucasians than African Americans reported a diagnosis of ET (1.7% vs. 0.4%; odds ratio = 4.9; 95% CI, 1.2-20.2; P = 0.028). In a logistic regression analysis, physician-diagnosed ET was associated with Caucasian ethnicity (P = 0.038) but not with age, gender, education, mental status or depression scores, income, smoking status, or alcohol consumption. When a standardized screening question was used, the proportion of participants with physician-diagnosed ET was similar across four communities, suggesting that the prevalence of this condition may be less variable than is often reported. Caucasians were five times more likely to have physician-diagnosed ET than were African Americans. This study does not provide an explanation for this difference, which deserves further study.

VL - 18 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14502671?dopt=Abstract ER - TY - JOUR T1 - Incidence and prevalence of dementia in the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2004 A1 - Fitzpatrick, Annette L A1 - Kuller, Lewis H A1 - Ives, Diane G A1 - Lopez, Oscar L A1 - Jagust, William A1 - Breitner, John C S A1 - Jones, Beverly A1 - Lyketsos, Constantine A1 - Dulberg, Corinne KW - African Americans KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Apolipoproteins E KW - Dementia KW - Dementia, Vascular KW - Education KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors KW - Sex Distribution KW - United States AB -

OBJECTIVES: To estimate the incidence and prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in the Cardiovascular Health Study (CHS) cohort.

DESIGN: Longitudinal cohort study using prospectively and retrospectively collected data to evaluate dementia.

SETTING: Four U.S. communities.

PARTICIPANTS: There were 3,602 CHS participants, including 2,865 white and 492 African-American participants free of dementia, who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years.

MEASUREMENTS: Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests, neurological examinations, medical records, physician questionnaires, and proxy/informant interviews. Demographics and apolipoprotein E (APOE) genotype were collected at baseline. Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD and Alzheimer's Disease Diagnostic and Treatment Center's State of California criteria for VaD.

RESULTS: Classification resulted in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up. Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women, 35.3 for white men, 58.8 for African-American women, and 53.0 for African-American men. Sex differences were not significant within race. Adjusted for age and education, racial differences were only of borderline significance and may have been influenced by ascertainment methodology. Rates differed substantially by educational attainment but were only significant for whites. Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4, compared with 29.6 for those without this allele (P<.001). In whites, type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans. At termination of observation, women had only a slightly higher prevalence of dementia (16.0%) than men (14.7%).

CONCLUSION: Sex and racial differences were not found, and VaD was higher than reported in other studies. These data provide new estimates of dementia incidence in a community sample for projection of future burden.

VL - 52 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14728627?dopt=Abstract ER - TY - JOUR T1 - Neighbourhood environments and mortality in an elderly cohort: results from the cardiovascular health study. JF - J Epidemiol Community Health Y1 - 2004 A1 - Diez Roux, Ana V A1 - Borrell, Luisa N A1 - Haan, Mary A1 - Jackson, Sharon A A1 - Schultz, Richard KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Income KW - Male KW - Poverty Areas KW - Residence Characteristics KW - Risk Factors KW - Socioeconomic Factors KW - United States AB -

BACKGROUND: 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.

VL - 58 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15483307?dopt=Abstract ER - TY - JOUR T1 - Predictors of falling cholesterol levels in older adults: the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 2004 A1 - Manolio, Teri A A1 - Cushman, Mary A1 - Gottdiener, John S A1 - Dobs, Adrian A1 - Kuller, Lewis H A1 - Kronmal, Richard A KW - African Americans KW - Age Factors KW - Aged KW - Cardiovascular Diseases KW - Cholesterol KW - European Continental Ancestry Group KW - Female KW - Forecasting KW - Health Status KW - Humans KW - Male KW - Medicare KW - Prospective Studies KW - Risk Factors KW - Sex Distribution KW - Sex Factors KW - United States AB -

PURPOSE: To estimate 4-year change in serum total cholesterol levels in a population-based sample of older adults and identify independent predictors of cholesterol decline.

METHODS: Prospective study of 2837 adults aged 65 years and older with serum cholesterol measured in 1992-1993 and 1996-1997.

RESULTS: Mean serum cholesterol levels declined 6.3 mg/dl between the two examinations. Declines were greater in white (-7.3 mg/dl) than black (-1.4 mg/dl) participants and in those in good/excellent health (-0.9 mg/dl) vs. fair/poor health (-3.1 mg/dl; both p < 0.01). Factors associated with greater decline on multivariate analysis included age, male gender, and higher white cell count, albumin, and baseline cholesterol. Cholesterol levels declined 2.0 mg/dl per 6 year increment in baseline age and 6.8 mg/dl more in men than women after adjustment for other factors. C-reactive protein levels were unrelated to cholesterol change.

CONCLUSION: Declining cholesterol levels were associated with male gender, advanced age, weight loss, and white blood cell count but not with C-reactive protein levels. The role of declining cholesterol synthesis, due to as yet undefined age-related changes or to cytokine-mediated reductions related to illness, should be examined to help clarify the mechanisms of the sometimes marked declines in cholesterol levels observed at advanced ages.

VL - 14 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15177271?dopt=Abstract ER - TY - JOUR T1 - Racial differences in endothelial function in postmenopausal women. JF - Am Heart J Y1 - 2004 A1 - Loehr, Laura R A1 - Espeland, Mark A A1 - Sutton-Tyrrell, Kim A1 - Burke, Gregory L A1 - Crouse, John R A1 - Herrington, David M KW - African Continental Ancestry Group KW - Aged KW - Brachial Artery KW - Cohort Studies KW - Endothelium, Vascular KW - European Continental Ancestry Group KW - Female KW - Humans KW - Multivariate Analysis KW - Postmenopause KW - Risk Factors KW - Vasodilation AB -

OBJECTIVE: Racial differences in cardiovascular mortality among women remain largely unexplained. Preliminary data suggest that African American and Caucasian differences in endothelial function may parallel differential cardiovascular disease (CVD) risk in women. To further study differences in endothelial function between African American and Caucasian women, we analyzed measures of brachial artery flow-mediated dilation (FMD) in women enrolled in the Cardiovascular Health Study (CHS).

METHODS AND RESULTS: Brachial artery FMD was measured in the fasting state using established ultrasound techniques in 1330 Caucasian and 297 African American female participants in CHS (mean age 78.4 +/- 4.4 years). General linear models were used to compare FMD between African American and Caucasian women after adjusting for baseline brachial diameter, hypertension, diabetes, smoking, cholesterol, systolic blood pressure, body mass index, waist/hip ratio, age, education, income level; use of angiotensin-converting enzyme inhibitors, beta-blockers, nitroglycerin, estrogens and lipid-lowering drugs; and presence of clinical or subclinical disease. Adjusted absolute change and percent change in brachial artery diameter was significantly reduced in African American women compared with Caucasian women (P <.0001 and P =.0002, respectively). Similar results were found when the women were stratified by history of CVD (- CVD, P =.02; + CVD, P =.001) and CVD or subclinical vascular disease (- disease, P =.01, + disease, P =.03).

CONCLUSIONS: In this cohort, brachial artery FMD was lower in African American women compared to Caucasian women, and this difference persisted after adjustment by multivariable analysis. The increased CVD risk in African American women may be related to impaired endothelial function. It remains to be determined whether African American women may uniquely benefit by interventions designed to improve endothelial health.

VL - 148 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15459590?dopt=Abstract ER - TY - JOUR T1 - Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study. JF - Am J Kidney Dis Y1 - 2005 A1 - Edwards, Matthew S A1 - Wilson, David B A1 - Craven, Timothy E A1 - Stafford, Jeanette A1 - Fried, Linda F A1 - Wong, Tien Y A1 - Klein, Ronald A1 - Burke, Gregory L A1 - Hansen, Kimberley J KW - African Americans KW - Aged KW - Aged, 80 and over KW - Aging KW - Antihypertensive Agents KW - Capillaries KW - Cohort Studies KW - Comorbidity KW - Creatinine KW - Diabetes Mellitus KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney KW - Male KW - Photography KW - Prospective Studies KW - Proteinuria KW - Retina KW - Retinal Diseases KW - Retinal Vessels AB -

BACKGROUND: Microvascular abnormalities in the kidney are common histopathologic findings in individuals with chronic kidney disease or renal failure. These abnormalities may represent one manifestation of ongoing systemic microvascular damage. We hypothesized that retinal microvascular abnormalities, when present, would be associated with progressive renal dysfunction in elderly individuals.

METHODS: The Cardiovascular Health Study (CHS) is a prospective, multicenter, cohort study initiated in 1989 designed to examine cardiovascular risk factors, morbidity, and mortality in elderly Americans. As part of an ancillary study, CHS participants underwent retinal photography in 1997 and 1998. Retinal microvascular abnormalities were assessed and graded by using standardized measures. Retinal microvascular abnormalities were defined as retinopathy (hard and soft exudates, hemorrhages, or microaneurysms) and/or retinal arteriolar abnormalities (arteriovenous nicking, focal arteriolar narrowing, or lowest quartile arteriole-venule ratio). Associations between these abnormalities and observed 4-year changes in serum creatinine levels and estimated glomerular filtration rates (eGFRs) from study years 5 to 9 (encompassing years 1994 to 2001) were examined by using regression modeling.

RESULTS: A total of 1,394 CHS participants had retinal and serum creatinine data. After adjustments for age, race, sex, weight, diabetes, hypertension, angiotensin-converting enzyme inhibitor use, and proteinuria, participants with retinopathy showed a significant increase in serum creatinine level and decline in eGFR compared with those without retinopathy during the 4-year study period (+0.24 mg/dL [+21 micromol/L] versus -0.21 mg/dL [-19 micromol/L] and -0.48 mL/min/1.73 m2 [-0.01 mL/s/1.73 m2] versus +1.74 mL/min/1.73 m2 [+0.03 mL/s/1.73 m2], respectively). Participants with retinopathy also were significantly more likely to have an observed significant deterioration in renal function, defined as a 0.3-mg/dL (27-micromol/L) increase in serum creatinine level or 20% or greater decline in eGFR (odds ratio, 3.20; 95% confidence interval, 1.58 to 6.50; and odds ratio, 2.84; 95% confidence interval, 1.56 to 5.16, respectively). These associations remained in separate stratified analyses of patients with and without diabetes. The presence of retinal arteriolar abnormalities was not associated with deteriorating renal function.

CONCLUSION: Retinal microvascular abnormalities defined as retinopathy were significantly associated with renal function deterioration. The observed findings were independent of effects of any associated diabetes or hypertension. These findings suggest that systemic microvascular disease may be associated with progressive renal dysfunction in the elderly population.

VL - 46 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16112039?dopt=Abstract ER - TY - JOUR T1 - beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2005 A1 - Hindorff, Lucia A A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Herrington, David M A1 - Edwards, Karen L A1 - Tracy, Russell P KW - African Americans KW - Antihypertensive Agents KW - Arteriosclerosis KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Homozygote KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Genetic KW - Receptors, Adrenergic, beta-2 KW - Risk Factors AB -

BACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.

METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.

RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.

CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.

VL - 18 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15797659?dopt=Abstract ER - TY - JOUR T1 - Incidence of cardiovascular disease in older Americans: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2005 A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Manolio, Teri A A1 - Fried, Linda P A1 - Robbins, John A A1 - Kronmal, Richard A KW - African Americans KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Geriatric Assessment KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Sex Distribution KW - Survival Rate KW - United States AB -

OBJECTIVES: To estimate incidence rates of major cardiovascular disease (CVD) in older Americans.

DESIGN: Longitudinal cohort study using prospectively collected data on cardiovascular events.

SETTING: Four U.S. communities in the Cardiovascular Health Study (CHS).

PARTICIPANTS: Five thousand eight hundred eighty-eight participants in CHS, aged 65 or older at enrollment, including 3,393 women (581 African American) and 2,495 men (343 African American).

MEASUREMENTS: At semiannual contacts, participants reported any occurrence of clinical CVD. Medical records were obtained and adjudicated to confirm diagnosis of CVD.

RESULTS: During 10 years of follow-up, incidence of coronary heart disease (CHD) per 1,000 person-years was 39.6 (95% confidence interval (CI)=36.4-43.1) in men and 22.3 (95% CI=20.4-24.2) in women. Cumulative event rates for CHD and myocardial infarction for women aged 75 and older at baseline were similar to those for men aged 65 to 74. The overall incidence of stroke was similar for men and women (14.7 (95% CI=13.0-16.6) and 13.7 (95% CI=12.4-15.1) per 1,000 person-years, respectively), but the risk of stroke increased with age more rapidly in women, resulting in a greater cumulative event rate for stroke in women than in men aged 75 and older. The incidence of congestive heart failure increased 9% with each year of age over 65 and was greater than 6% per year in Caucasian men and women aged 85 and older at baseline. Rates were similar in African Americans and Caucasians.

CONCLUSION: The occurrence of new CVD in older Americans is high, indicating that preventive efforts need to be maintained into older ages.

VL - 53 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15673343?dopt=Abstract ER - TY - JOUR T1 - Renal duplex parameters, blood pressure, and renal function in elderly people. JF - Am J Kidney Dis Y1 - 2005 A1 - Pearce, Jeffrey D A1 - Edwards, Matthew S A1 - Craven, Timothy E A1 - English, William P A1 - Mondi, Matthew M A1 - Reavis, Scott W A1 - Hansen, Kimberley J KW - African Americans KW - Aged KW - Aging KW - Arteriosclerosis KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - Cross-Sectional Studies KW - Diastole KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension, Renovascular KW - Kidney KW - Kidney Diseases KW - Kidney Function Tests KW - Male KW - Renal Artery KW - Renal Artery Obstruction KW - Renal Circulation KW - Risk Factors KW - Sampling Studies KW - Systole KW - Ultrasonography, Doppler, Duplex KW - United States AB -

BACKGROUND: Changes in renal artery and renal parenchyma perfusion are believed to correlate with severity of hypertension and worsened renal function, but population-based studies of these associations are not available. This study examines relationships between parameters derived from renal duplex sonography (RDS), blood pressure (BP), and excretory renal function in a population-based cohort of elderly Americans.

METHODS: Through an ancillary study to the Cardiovascular Health Study, 758 participants (37% men; mean age, 77 years) underwent RDS in which flow velocities and frequency shifts were determined from spectral analysis of Doppler-shifted signals obtained from the renal artery and parenchyma. Associations of these duplex parameters with BP and inverse serum creatinine were examined by using multivariate regression techniques.

RESULTS: Main renal artery peak systolic flow velocity (PSV) showed independent associations with BP, with an SD increase in PSV (0.53 m/s) associated with a 3.3-mm Hg increase in systolic BP (SBP) and a 2.4-mm Hg decrease in diastolic BP (DBP). An SD decrease in end-diastolic frequency shift (EDF; 131 kHz) was associated with a 6.0-mm Hg increase in SBP, a 4.2-mm Hg decrease in DBP, and a significant 3.7% decrease in inverse serum creatinine.

CONCLUSION: Increases in renal artery PSV and decreases in parenchymal EDF are associated with increased SBP and decreased DBP. Moreover, decreased parenchymal EDF showed significant associations with impaired excretory renal function. These results suggest that renal duplex parameters are associated with renal parenchymal changes caused by hypertension and progressive renal dysfunction in elderly people.

VL - 45 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15861349?dopt=Abstract ER - TY - JOUR T1 - 10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2006 A1 - Kuller, Lewis H A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Robbins, John A A1 - O'Leary, Daniel H A1 - Tracy, Russell P A1 - Burke, Gregory L A1 - Manolio, Teri A A1 - Chaves, Paolo H M KW - African Continental Ancestry Group KW - Aged KW - Blood Chemical Analysis KW - Cardiovascular Diseases KW - Comorbidity KW - Coronary Disease KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Prevalence KW - Proportional Hazards Models KW - Regression Analysis KW - Risk Factors KW - Sex Distribution KW - United States AB -

BACKGROUND: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older.

METHODS: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study.

RESULTS: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals.

CONCLUSIONS: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus.

VL - 166 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16401813?dopt=Abstract ER - TY - JOUR T1 - Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JF - JAMA Y1 - 2006 A1 - Lange, Leslie A A1 - Carlson, Christopher S A1 - Hindorff, Lucia A A1 - Lange, Ethan M A1 - Walston, Jeremy A1 - Durda, J Peter A1 - Cushman, Mary A1 - Bis, Joshua C A1 - Zeng, Donglin A1 - Lin, Danyu A1 - Kuller, Lewis H A1 - Nickerson, Deborah A A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Reiner, Alexander P KW - African Continental Ancestry Group KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Carotid Arteries KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Male KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk KW - Stroke KW - Tunica Intima AB -

CONTEXT: C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD).

OBJECTIVE: To assess whether polymorphisms in the CRP gene are associated with plasma CRP, carotid intima-media thickness (CIMT), and CVD events.

DESIGN, SETTING, AND PARTICIPANTS: In the prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs) (1919A/T, 2667G/C, 3872G/A, 5237A/G) were genotyped in 3941 white (European American) participants and 5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003).

MAIN OUTCOME MEASURES: Baseline CIMT; occurrence of MI, stroke, and CVD mortality during follow-up.

RESULTS: In white participants, 461 incident MIs, 491 incident strokes, and 490 CVD-related deaths occurred; in black participants, 67 incident MIs, 78 incident strokes, and 75 CVD-related deaths occurred. The 1919T and 790T alleles were associated with higher CRP levels in white and black participants, respectively. The 3872A allele was associated with lower CRP levels in both populations, and the 2667C allele was associated with lower CRP levels in white participants only. There was no association between CIMT and any CRP gene polymorphism in either population. In white participants, the 1919T allele was associated with increased risk of stroke for TT vs AA (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.87) and for CVD mortality (HR, 1.40; 95% CI, 1.10-1.90). In black participants, homozygosity for the 790T allele was associated with a 4-fold increased risk of MI compared with homozygosity for the 790A allele (95% CI, 1.58-10.53). The minor alleles of the 2 SNPs associated with lower plasma CRP concentration in white participants (2667C and 3872A) were associated with decreased risk of CVD mortality.

CONCLUSIONS: Genetic variation in the CRP gene is associated with plasma CRP levels and CVD risk in older adults.

VL - 296 IS - 22 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17164456?dopt=Abstract ER - TY - JOUR T1 - The association of race with frailty: the cardiovascular health study. JF - Ann Epidemiol Y1 - 2006 A1 - Hirsch, Calvin A1 - Anderson, Melissa L A1 - Newman, Anne A1 - Kop, Willem A1 - Jackson, Sharon A1 - Gottdiener, John A1 - Tracy, Russell A1 - Fried, Linda P KW - African Americans KW - Aged KW - Asthenia KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Frail Elderly KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Motor Activity KW - Odds Ratio KW - United States KW - Weight Loss AB -

PURPOSE: Frailty, which has been conceptualized as a state of decreased physiologic reserve contributing to functional decline, has a prevalence among older African Americans that is twice that in older whites. This study assesses the independent contribution of race to frailty.

METHODS: We evaluated 786 African-American and 4491 white participants of the Cardiovascular Health Study (CHS). Frailty is defined as meeting three or more of five criteria derived from CHS measures: lowest quintile for grip strength, self-reported exhaustion, unintentional weight loss of 10 lbs or greater in 1 year, slowest quintile for gait speed, and lowest quintile for physical activity. Controlling for age, sex, comorbidity, socioeconomic factors, and race, multinomial logistic regression estimated the odds ratio (OR) of prefrail (one or two criteria) to not frail and frail to not frail.

RESULTS: Among African Americans, 8.7% of men and 15.0% of women were frail compared with 4.6% and 6.8% of white men and women, respectively. In adjusted models, nonobese African Americans had a fourfold greater odds of frailty compared with whites. The increased OR of frailty associated with African-American race was less pronounced among those who were obese or disabled.

CONCLUSION: African-American race is associated independently with frailty.

VL - 16 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16388967?dopt=Abstract ER - TY - JOUR T1 - Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. JF - Circulation Y1 - 2006 A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Vatta, Matteo A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Towbin, Jeffrey A A1 - Lemaitre, Rozenn N A1 - Rea, Thomas D A1 - Durda, J Peter A1 - Chang, Joel M A1 - Lumley, Thomas S A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Heckbert, Susan R KW - African Continental Ancestry Group KW - Aged KW - Case-Control Studies KW - Death, Sudden, Cardiac KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glutamine KW - Haplotypes KW - Homozygote KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Receptors, Adrenergic, beta-2 KW - Reproducibility of Results AB -

BACKGROUND: Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.

METHODS AND RESULTS: In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.

CONCLUSIONS: Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.

VL - 113 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16618831?dopt=Abstract ER - TY - JOUR T1 - Education, cognitive test scores, and black-white differences in dementia risk. JF - J Am Geriatr Soc Y1 - 2006 A1 - Shadlen, Marie-Florence A1 - Siscovick, David A1 - Fitzpatrick, Annette L A1 - Dulberg, Corinne A1 - Kuller, Lewis H A1 - Jackson, Sharon KW - African Continental Ancestry Group KW - Aged KW - Cognition KW - Dementia KW - Educational Status KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Psychological Tests KW - Retrospective Studies KW - Risk Factors KW - United States AB -

OBJECTIVES: To compare dementia risks of elderly black and white subjects and to determine whether differences in education and cognitive test scores contribute to the inconsistency in reported differences between these groups.

DESIGN: Longitudinal, 6-year follow-up.

PARTICIPANTS: Two thousand seven hundred eighty-six older black and white subjects in the Cardiovascular Health Study.

MEASUREMENTS: Age, education (>10 years vs < or =10 years), Modified Mini-Mental State Examination score (3MS, < or =85 vs >85). Potential confounders were sex, depression, apolipoprotein E4 genotype, vascular disease, and baseline magnetic resonance imaging changes.

RESULTS: White subjects with low education and black subjects with high education had twice the risk of dementia of white subjects with high education (95% confidence interval (CI)=1.5-2.4 and 95% CI=1.4-2.7); black subjects with low education had five times the risk of dementia (95% CI=3.4-7.7). Likewise, for subjects with low 3MSE scores, black subjects had 6.7 times the risk of dementia (95% CI=4.7-9.7) and white subjects had 2.7 times the risk of dementia (95% CI=2.2-3.5) as white subjects with high 3MSE scores. Finally, in Cox models, there was no significant black-white difference in dementia risk after adjustment for all confounders and baseline 3MSE.

CONCLUSION: Black race was associated with greater dementia risk even after adjustment for education and other potential confounders. This black-white difference in dementia risk was markedly attenuated after adjustment for baseline cognitive screening scores. The apparent race effect may reflect gaps in the quality of education or differences in the trajectory of impaired cognitive function experienced by the two groups. Future investigations might take these findings into consideration for the design of studies evaluating black-white differences in dementia risk.

VL - 54 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16776783?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation. JF - Metabolism Y1 - 2006 A1 - Miljkovic-Gacic, Iva A1 - Bunker, Clareann H A1 - Ferrell, Robert E A1 - Kammerer, Candace M A1 - Evans, Rhobert W A1 - Patrick, Alan L A1 - Kuller, Lewis H KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Alleles KW - Body Mass Index KW - Cardiovascular Diseases KW - Caribbean Region KW - Cohort Studies KW - DNA KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Humans KW - Lipase KW - Lipoproteins KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Liver KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Particle Size KW - Trinidad and Tobago KW - United States AB -

Despite a higher prevalence of coronary heart disease risk factors, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than whites. In part, this is thought to be because of the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower triglycerides and higher high-density lipoprotein (HDL) cholesterol. We hypothesized that the -514C>T polymorphism in the hepatic lipase gene (LIPC) plays a significant role in determining a less atherogenic lipoprotein profile observed in men of African origin. Previously conducted studies of the LIPC -514C>T polymorphism in African Americans may have been confounded by a higher level of European admixture; in addition, the results from these studies do not necessarily apply to other African populations because gene-environment interactions may differ. Thus, we compared nuclear magnetic resonance spectroscopy-measured lipoprotein subclass patterns and LIPC -514C>T genotypes in population-based samples of older white American (n = 532) and African American (n = 97) men from the Cardiovascular Health Study to those among older, less admixed, Afro-Caribbean men (n = 205) from the Tobago Health Study. Men of African origin had a more favorable lipoprotein profile than whites. In addition, levels of low-density lipoprotein cholesterol, total cholesterol, and triglyceride, and large and small very low-density lipoprotein, small low-density lipoprotein, as well as very low-density lipoprotein particle size, were remarkably lower in Afro-Caribbean men than in either African American or white men. The frequency of the LIPC -514T allele was much higher in Afro-Caribbeans (0.57) and in African Americans (0.49) than in whites (0.20). The -514T allele in both populations of African origin, but not in whites, was associated with elevated large HDL and greater HDL size. Our findings indicate that the higher frequency of the LIPC -514T allele found in men of African origin living in different environments significantly contributes to the more favorable distribution of HDL subclasses compared with whites.

VL - 55 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16324926?dopt=Abstract ER - TY - JOUR T1 - Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2006 A1 - McNeill, Ann Marie A1 - Katz, Ronit A1 - Girman, Cynthia J A1 - Rosamond, Wayne D A1 - Wagenknecht, Lynne E A1 - Barzilay, Joshua I A1 - Tracy, Russell P A1 - Savage, Peter J A1 - Jackson, Sharon A KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Humans KW - Incidence KW - Male KW - Metabolic Syndrome KW - Risk Factors KW - Sex Factors AB -

OBJECTIVES: To assess the prospective association between metabolic syndrome (MetS) and cardiovascular disease (CVD) in older people and to evaluate the effect of lowering the threshold for impaired fasting glucose (IFG) on the prevalence of IFG and MetS and the risk of CVD.

DESIGN: Prospective cohort study.

SETTING: Four field centers in U.S. communities.

PARTICIPANTS: Three thousand five hundred eighty-five subjects in the Cardiovascular Health Study free of diabetes mellitus and CVD at baseline (mean age 72, 62% female, 14% black).

MEASUREMENTS: Baseline measures of MetS components and adjudicated incident CVD events. MetS (2001) was defined first using the original criteria from the Third Adult Treatment Panel Report of the National Cholesterol Education Program (> or =3 of the following: large waist circumference (women >88 cm, men >102 cm), elevated triglycerides (> or =1.70 mmol/L), low high-density lipoprotein cholesterol (men <1.04 mmol/L, women <1.30 mmol/L), elevated fasting glucose (6.1-6.9 mmol/L), and high blood pressure (> or =130/85 mmHg or self-reported use of medications for hypertension). Subjects were also classified according to the revised definition of the MetS (2005) that applies the lower threshold for fasting glucose (5.6-6.9 mmol/L).

RESULTS: During follow-up (median 11 years), 818 coronary heart disease (CHD), 401 stroke, and 554 congestive heart failure (CHF) events occurred. Age- and race-adjusted hazard ratios (HRs) for CHD, stroke, and CHF were 1.30 (95% confidence interval (CI) = 1.07-1.57), 0.94 (95% CI = 0.73-1.21), and 1.40 (95% CI = 1.12-1.76) for women and 1.35 (95% CI = 1.10-1.66), 1.51 (95% CI = 1.08-2.12), and 1.47 (95% CI = 1.14-1.90) for men, respectively. Overall, women and men with MetS (2005) were 20% to 30% more likely to experience any CVD event than subjects without MetS (2005). Using the lower cut-point for IFG resulted in a near tripling in IFG prevalence (16% to 46%) and an additional 9% classified with MetS (2005) but HRs similar to those estimated from the original MetS (2001) criteria. High blood pressure was the component most strongly associated with incident CHD.

CONCLUSION: Results from this study of an elderly, population-based cohort provide support for earlier investigations in primarily middle-aged populations that link the presence of MetS with the development of CVD and further underscore the importance of recognizing and treating its individual components, particularly high blood pressure.

VL - 54 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16970637?dopt=Abstract ER - TY - JOUR T1 - Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study. JF - Arch Ophthalmol Y1 - 2007 A1 - Tikellis, Gabriella A1 - Sun, Cong A1 - Gorin, Michael B A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Larsen, Emily K Marino A1 - Siscovick, David S A1 - Hubbard, Larry D A1 - Wong, Tien Y KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alleles KW - Apolipoprotein E2 KW - Apolipoprotein E3 KW - Apolipoprotein E4 KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Macular Degeneration KW - Male KW - Odds Ratio KW - Polymorphism, Genetic KW - Risk Factors AB -

OBJECTIVE: To examine the association between the apolipoprotein E (APOE) gene and age-related maculopathy (ARM) in an older population.

METHODS: Two thousand one hundred seventy persons 65 years and older sampled from 4 US communities had ARM signs assessed from retinal photographs using a modified Wisconsin Age-Related Maculopathy Grading System. DNA extracted from blood samples was analyzed for common APOE alleles.

RESULTS: After controlling for age, sex, cigarette smoking, and other factors, white participants carrying the epsilon2 allele had an increased risk of late ARM (odds ratio, 2.53 [95% confidence interval, 1.08-5.90]) while carriers of the epsilon4 allele had a lower risk of late ARM (odds ratio, 0.69 [95% confidence interval, 0.19-2.50]). There were too few late ARM cases in African American individuals for analysis.

CONCLUSION: APOE polymorphism is associated with late ARM in older white persons 65 years and older. Consistent with previous studies, the APOE epsilon2 allele is associated with a significant increased risk of late ARM development, whereas the epsilon4 allele may confer some protection.

VL - 125 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17210854?dopt=Abstract ER - TY - JOUR T1 - Apolipoprotein E gene and retinal microvascular signs in older people: the Cardiovascular Health Study. JF - Mol Vis Y1 - 2007 A1 - Sun, Cong A1 - Tikellis, Gabriella A1 - Liew, Gerald A1 - Klein, Ronald A1 - Larsen, Emily K Marino A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Apolipoprotein E2 KW - Apolipoprotein E4 KW - Apolipoproteins E KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genotype KW - Heterozygote KW - Homozygote KW - Humans KW - Male KW - Microcirculation KW - Polymorphism, Genetic KW - Retinal Diseases KW - Retinal Vessels AB -

PURPOSE: To examine the association between apolipoprotein E (APOE) gene polymorphism and retinal microvascular signs in an older population.

METHODS: Retinal photographs were taken of 2,152 participants (1,831 whites, and 321 African-Americans), aged 69-96 years, who were participating in a population-based study of four United States communities. We used standardized protocols to assess photographs for the presence of retinal microvascular signs (retinopathy, arterio-venous nicking, and focal arteriolar narrowing) and a computer-assisted method to measure retinal vessel diameters. We analyzed DNA extracted from blood samples of participants for common allelic variants of the APOE gene.

RESULTS: After adjusting for age, gender, systolic blood pressure, smoking, total serum cholesterol, and other risk factors, we found white participants carrying the epsilon2 and epsilon4 alleles were more likely to have arterio-venous nicking than the epsilon3/epsilon3 homozygotes, with odds ratio (OR) of 1.70 and confidence interval (CI) 95% (1.03-2.83) for the epsilon2 carriers and OR 1.74 (95% CI 1.06-2.84) for the epsilon4 carriers. Among white participants without hypertension, the associations remained significant for the epsilon4 carriers (OR 2.32, 95% CI 1.18-4.57). Whites, normotensive carriers of the epsilon2 allele had significantly narrower retinal arteriolar diameters (adjusted mean arteriolar diameter of 163.5 mum, 95% CI 160.1-167.0, p=0.03) compared to the epsilon3/epsilon3 homozygotes (167.8 mum, 95% CI 166.0-169.6). APOE gene polymorphism was not associated with retinopathy, focal narrowing, or retinal venular diameters in white participants. There were insufficient numbers of African-Americans for separate multivariate analysis.

CONCLUSIONS: This study provides little evidence that the APOE gene polymorphism plays a significant role in the pathogenesis of retinal microvascular changes in the general population. In the older white population, APOE epsilon2 and epsilon4 allele carriers were more likely to have arterio-venous nicking. Other retinal signs, however, were not related to APOE gene polymorphism.

VL - 13 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18079687?dopt=Abstract ER - TY - JOUR T1 - The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study. JF - Thromb Res Y1 - 2007 A1 - Rasmussen-Torvik, Laura J A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Zhang, Yan A1 - Heckbert, Susan R A1 - Rosamond, Wayne D A1 - Folsom, Aaron R KW - African Continental Ancestry Group KW - Aged KW - Case-Control Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genotype KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Mutation, Missense KW - Polymorphism, Genetic KW - Venous Thromboembolism AB -

INTRODUCTION: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study.

MATERIALS AND METHODS: 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE.

RESULTS: In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors.

CONCLUSIONS: These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.

VL - 121 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17433418?dopt=Abstract ER - TY - JOUR T1 - Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. JF - Circulation Y1 - 2007 A1 - Cao, Jie J A1 - Arnold, Alice M A1 - Manolio, Teri A A1 - Polak, Joseph F A1 - Psaty, Bruce M A1 - Hirsch, Calvin H A1 - Kuller, Lewis H A1 - Cushman, Mary KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - Cohort Studies KW - Comorbidity KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Incidence KW - Inflammation KW - Kaplan-Meier Estimate KW - Male KW - Mass Screening KW - Mortality KW - Myocardial Infarction KW - Obesity KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - ROC Curve KW - Smoking KW - Stroke KW - Survival Analysis KW - Tunica Intima KW - Tunica Media KW - Ultrasonography KW - United States AB -

BACKGROUND: Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction.

METHODS AND RESULTS: Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged > or = 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72% (95% CI, 1.46 to 2.01) increased risk for CVD death and a 52% (95% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54% for CVD death and 79% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic.

CONCLUSIONS: In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors.

VL - 116 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17576871?dopt=Abstract ER - TY - JOUR T1 - IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. JF - Hum Genet Y1 - 2007 A1 - Walston, Jeremy D A1 - Fallin, M Daniele A1 - Cushman, Mary A1 - Lange, Leslie A1 - Psaty, Bruce A1 - Jenny, Nancy A1 - Browner, Warren A1 - Tracy, Russell A1 - Durda, Peter A1 - Reiner, Alex KW - African Americans KW - Aged KW - Alleles KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - Interleukin-6 KW - Introns KW - Longitudinal Studies KW - Male KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic AB -

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

VL - 122 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17851695?dopt=Abstract ER - TY - JOUR T1 - USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies. JF - Arterioscler Thromb Vasc Biol Y1 - 2007 A1 - Reiner, Alexander P A1 - Carlson, Christopher S A1 - Jenny, Nancy S A1 - Durda, J Peter A1 - Siscovick, David S A1 - Nickerson, Deborah A A1 - Tracy, Russell P KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - C-Reactive Protein KW - Calcium KW - Cardiovascular Diseases KW - Carotid Artery, Common KW - Cohort Studies KW - Coronary Artery Disease KW - Coronary Vessels KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Predisposition to Disease KW - Humans KW - Hyperlipidemia, Familial Combined KW - Insulin KW - Interleukin-6 KW - Linkage Disequilibrium KW - Lipids KW - Male KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States KW - Upstream Stimulatory Factors AB -

OBJECTIVE: A common haplotype of the upstream transcription factor 1 gene (USF1) has been associated with decreased susceptibility to familial combined hyperlipidemia (FCHL) and, paradoxically, with increased risk of cardiovascular disease (CVD) and all-cause mortality.

METHODS AND RESULTS: We assessed associations between USF1 tagSNPs, CVD risk factors, and aging-related phenotypes using data from 2 large population-based cohorts, Coronary Artery Risk Development in Young Adults (CARDIA) and the Cardiovascular Health Study (CHS), comprising younger and older adults, respectively. In CARDIA, each additional copy of the FCHL low-risk allele was associated with 2.4 mg/dL lower levels of LDL cholesterol (P=0.01) and decreased risk of subclinical atherosclerosis as assessed by coronary artery calcium (odds ratio 0.79; 95%CI 0.63 to 0.98). Whereas there was little association between USF1 genotype and metabolic or CVD traits in older adults from CHS, the USF1 low-risk dyslipidemia allele was associated with higher plasma C-reactive protein and interleukin (IL)-6 levels and with increased risk of mortality, particularly attributable to noncardiovascular causes.

CONCLUSIONS: There appears to be a complex and possibly age-dependent relationship between USF1 genotype, atherosclerosis phenotypes, and CVD risk. USF1 may influence mortality through pathways distinct from atherosclerosis. Alternatively, linkage disequilibrium with neighboring polymorphisms in other genes such as F11R may be responsible for the observed USF1 genotype-phenotype associations in older adults.

VL - 27 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17885212?dopt=Abstract ER - TY - JOUR T1 - White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study. JF - Neurobiol Aging Y1 - 2007 A1 - Kuller, Lewis H A1 - Arnold, Alice M A1 - Longstreth, W T A1 - Manolio, Teri A A1 - O'Leary, Daniel H A1 - Burke, Gregory L A1 - Fried, Linda P A1 - Newman, Anne B KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Brain KW - Cardiovascular Diseases KW - Cerebral Ventricles KW - European Continental Ancestry Group KW - Female KW - Geriatric Assessment KW - Health Status KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Retrospective Studies KW - Risk Factors KW - Sex Factors AB -

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (n=3245) mean age 75 years, 50% black and 40% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10-12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.

VL - 28 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16857296?dopt=Abstract ER - TY - JOUR T1 - Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 2008 A1 - Shiffman, Dov A1 - O'Meara, Ellen S A1 - Bare, Lance A A1 - Rowland, Charles M A1 - Louie, Judy Z A1 - Arellano, Andre R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Iakoubova, Olga A1 - Luke, May M A1 - Young, Bradford A A1 - Malloy, Mary J A1 - Kane, John P A1 - Ellis, Stephen G A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Americans KW - Aged KW - Aged, 80 and over KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - United States AB -

OBJECTIVE: We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older.

METHODS AND RESULTS: Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P<0.05) with increased risk of MI in White CHS participants. The false discovery rate for these 8 was 0.43, suggesting that about 4 of these 8 are likely to be true positives. The 4 of these 8 SNPs that had the strongest evidence for association with cardiovascular disease before testing in CHS (association in 3 antecedent studies) were in KIF6 (CHS HR=1.29; 90%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90%CI 1 to 1.27), and LPA (HR=1.62; 90%CI 1.09 to 2.42).

CONCLUSIONS: Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.

VL - 28 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17975119?dopt=Abstract ER - TY - JOUR T1 - Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study. JF - Thromb Haemost Y1 - 2008 A1 - Carty, Cara L A1 - Cushman, Mary A1 - Jones, Daniel A1 - Lange, Leslie A A1 - Hindorff, Lucia A A1 - Rice, Kenneth A1 - Jenny, Nancy S A1 - Durda, J Peter A1 - Walston, Jeremy A1 - Carlson, Christopher S A1 - Nickerson, Debbie A1 - Tracy, Russell P A1 - Reiner, Alex P KW - African Americans KW - Age Factors KW - Aged KW - Brain Ischemia KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Population Surveillance KW - Proportional Hazards Models KW - Prospective Studies KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Stroke KW - United States AB -

Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (> or = 5% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European- (EA) and African-descent (AA) adults (> or = 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807, FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437; each additional copy of the minor allele was associated with 13 mg/dl (95%CI: 9-16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR = 1.9 (95%CI: 1.3-2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.

VL - 99 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18278190?dopt=Abstract ER - TY - JOUR T1 - Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. JF - Stroke Y1 - 2008 A1 - Fornage, Myriam A1 - Chiang, Y Aron A1 - O'Meara, Ellen S A1 - Psaty, Bruce M A1 - Reiner, Alexander P A1 - Siscovick, David S A1 - Tracy, Russell P A1 - Longstreth, W T KW - African Continental Ancestry Group KW - Aged KW - Biomarkers KW - Brain Infarction KW - C-Reactive Protein KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Haplotypes KW - Humans KW - Inflammation KW - Interleukin-6 KW - Magnetic Resonance Imaging KW - Male KW - Polymorphism, Single Nucleotide AB -

BACKGROUND AND PURPOSE: To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.

METHODS: Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905).

RESULTS: Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the -174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the -572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.

CONCLUSIONS: This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

VL - 39 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18436879?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adults. JF - J Thromb Haemost Y1 - 2008 A1 - Lange, L A A1 - Reiner, A P A1 - Carty, C L A1 - Jenny, N S A1 - Cushman, M A1 - Lange, E M KW - Africa KW - African Americans KW - Aged KW - Aged, 80 and over KW - Blood Coagulation KW - Europe KW - European Continental Ancestry Group KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Fibrinolysis KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - United States KW - Urokinase-Type Plasminogen Activator AB -

BACKGROUND AND OBJECTIVES: D-dimer is a hemostasis marker that reflects ongoing fibrin formation and degradation. There is significant inter-individual and inter-population variability in D-dimer concentration, but whether genetic factors underlie these differences is largely unknown. We hypothesized that common coagulation gene variants contribute to differences in circulating D-dimer concentration.

METHODS: The setting was European-American (EA; n = 1858) and African-American (AA; n = 327) unrelated older adults from the Cardiovascular Health Study (CHS), in which we genotyped SNPs in 42 genes related to blood coagulation and fibrinolysis.

RESULTS: Several fibrinogen gene polymorphisms, including the Thr312Ala Aalpha chain variant and the FGG-10034 C/T variant, were associated with approximately 20% higher plasma D-dimer levels in EA (false discovery rate < 5% for covariate-adjusted model). There was also some evidence that a Pro41Leu variant of the PLAU gene encoding urinary plasminogen activator and non-coding polymorphism of the plasminogen activator inhibitor type 1 gene (SERPINE1) were associated with higher plasma D-dimer in EA. There were no significant associations between the studied coagulation or fibrinolysis gene SNPs and plasma D-dimer levels in the smaller AA sample. However, each standard deviation increase in European ancestry assessed by ancestry-informative gene markers was associated with approximately 10% lower mean D-dimer levels in AA.

CONCLUSIONS: Together, common coagulation/fibrinolysis gene SNPs explained only approximately 2% of the variance in plasma D-dimer levels in EA. These findings suggest that the association of D-dimer with risk of vascular outcomes may be mediated largely by environmental factors, other genes, and/or genetic interactions.

VL - 6 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18208536?dopt=Abstract ER - TY - JOUR T1 - Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. JF - Arch Neurol Y1 - 2008 A1 - Irie, Fumiko A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Peila, Rita A1 - Newman, Anne B A1 - Launer, Lenore J KW - African Americans KW - Age Factors KW - Aged KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Cognition KW - Cohort Studies KW - Confidence Intervals KW - Dementia, Vascular KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors AB -

BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes.

OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD.

DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors.

RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95% confidence interval, 1.46-10.40).

CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.

VL - 65 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18195144?dopt=Abstract ER - TY - JOUR T1 - Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. JF - Ophthalmology Y1 - 2009 A1 - Sun, Cong A1 - Klein, Ronald A1 - Wong, Tien Y KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cholesterol, LDL KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Macular Degeneration KW - Male KW - Prospective Studies KW - Risk Factors KW - Sex Factors KW - Stroke KW - Triglycerides KW - United States AB -

PURPOSE: To examine the associations of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and stroke in the Cardiovascular Health Study.

DESIGN: Population-based prospective cohort study.

PARTICIPANTS: A total of 1786 white and African-American participants free of CHD or 2228 participants free of stroke, aged 69 to 97 years.

METHODS: AMD was evaluated from photographs taken in 1997 and 1998.

MAIN OUTCOME MEASURES: Incident CHD and stroke ascertained using standardized methods.

RESULTS: Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. Participants with early AMD (n = 277) had a higher cumulative incidence of CHD than participants without early AMD (25.8% vs. 18.9%, P = 0.001). By adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein, the presence of early AMD was associated with an increased risk of incident CHD (hazard ratio 1.57; 95% confidence interval, 1.17-2.22). Late AMD (n = 25) was not associated with incident CHD (hazard ratio 0.78; 95% confidence interval, 0.25-2.48). Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke.

CONCLUSIONS: This study suggests persons with early AMD have a higher risk of CHD but not stroke in a population aged 69 to 97 years. This provides further support that AMD is associated with underlying systemic vascular disease.

VL - 116 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19592102?dopt=Abstract ER - TY - JOUR T1 - Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Dehghan, Abbas A1 - Yang, Qiong A1 - Peters, Annette A1 - Basu, Saonli A1 - Bis, Joshua C A1 - Rudnicka, Alicja R A1 - Kavousi, Maryam A1 - Chen, Ming-Huei A1 - Baumert, Jens A1 - Lowe, Gordon D O A1 - McKnight, Barbara A1 - Tang, Weihong A1 - de Maat, Moniek A1 - Larson, Martin G A1 - Eyhermendy, Susana A1 - McArdle, Wendy L A1 - Lumley, Thomas A1 - Pankow, James S A1 - Hofman, Albert A1 - Massaro, Joseph M A1 - Rivadeneira, Fernando A1 - Kolz, Melanie A1 - Taylor, Kent D A1 - van Duijn, Cornelia M A1 - Kathiresan, Sekar A1 - Illig, Thomas A1 - Aulchenko, Yurii S A1 - Volcik, Kelly A A1 - Johnson, Andrew D A1 - Uitterlinden, André G A1 - Tofler, Geoffrey H A1 - Gieger, Christian A1 - Psaty, Bruce M A1 - Couper, David J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C A1 - Strachan, David P A1 - Smith, Nicholas L A1 - Folsom, Aaron R KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract ER - TY - JOUR T1 - Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascula JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Reiner, Alexander P A1 - Gross, Myron D A1 - Carlson, Christopher S A1 - Bielinski, Suzette J A1 - Lange, Leslie A A1 - Fornage, Myriam A1 - Jenny, Nancy S A1 - Walston, Jeremy A1 - Tracy, Russell P A1 - Williams, O Dale A1 - Jacobs, David R A1 - Nickerson, Deborah A KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, LDL KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - gamma-Glutamyltransferase KW - Genetic Predisposition to Disease KW - Genotype KW - Hepatocyte Nuclear Factor 1-alpha KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 alpha regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 alpha gene (HNF1A) were recently associated with plasma C-reactive protein and gamma-glutamyl transferase concentration in middle-aged to older European Americans (EA).

METHODS AND RESULTS: We assessed whether common variants of HNF1A are associated with C-reactive protein, gamma-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and gamma-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA.

CONCLUSIONS: Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.

VL - 2 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031592?dopt=Abstract ER - TY - JOUR T1 - Common variants at ten loci influence QT interval duration in the QTGEN Study. JF - Nat Genet Y1 - 2009 A1 - Newton-Cheh, Christopher A1 - Eijgelsheim, Mark A1 - Rice, Kenneth M A1 - de Bakker, Paul I W A1 - Yin, Xiaoyan A1 - Estrada, Karol A1 - Bis, Joshua C A1 - Marciante, Kristin A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Sotoodehnia, Nona A1 - Smith, Nicholas L A1 - Rotter, Jerome I A1 - Kors, Jan A A1 - Witteman, Jacqueline C M A1 - Hofman, Albert A1 - Heckbert, Susan R A1 - O'Donnell, Christopher J A1 - Uitterlinden, André G A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Larson, Martin G A1 - Stricker, Bruno H Ch KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Chromosome Mapping KW - Death, Sudden, Cardiac KW - Electroencephalography KW - ERG1 Potassium Channel KW - Ether-A-Go-Go Potassium Channels KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome, Human KW - Humans KW - KCNQ1 Potassium Channel KW - Meta-Analysis as Topic KW - Muscle Proteins KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Voltage-Gated KW - Risk Factors KW - Sodium Channels AB -

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

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

Inflammation is believed to play a role in prostate cancer (PCa) etiology, but it is unclear whether inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) associate with PCa risk in older men. Using Cox regression, we assessed the relationship between baseline concentrations of CRP and IL-6 and the subsequent PCa risk in the Cardiovascular Health Study, a population-based cohort study of mostly European American men of ages >64 years (n = 2,234; mean follow-up = 8.7 years; 215 incident PCa cases). We also tested associations between CRP and IL-6 tagSNPs and PCa risk, focusing on SNPs that are known to associate with circulating CRP and/or IL-6. Neither CRP nor IL-6 blood concentrations was associated with PCa risk. The C allele of IL-6 SNP rs1800795 (-174), a known functional variant, was associated with increased risk in a dominant model (HR = 1.44; 95% CI = 1.03-2.01; p = 0.03), but was not statistically significant after accounting for multiple tests (permutation p = 0.21). Our results suggest that circulating CRP and IL-6 do not influence PCa risk. SNPs at the CRP locus are not associated with PCa risk in this cohort, while the association between rs1800795 and PCa risk warrants further investigation.

VL - 20 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19267250?dopt=Abstract ER - TY - JOUR T1 - Gene variants associated with ischemic stroke: the cardiovascular health study. JF - Stroke Y1 - 2009 A1 - Luke, May M A1 - O'Meara, Ellen S A1 - Rowland, Charles M A1 - Shiffman, Dov A1 - Bare, Lance A A1 - Arellano, Andre R A1 - Longstreth, W T A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Brain Ischemia KW - Cardiovascular Diseases KW - Coronary Disease KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Variation KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.

METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).

RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS.

CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.

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

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

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

BACKGROUND: The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study.

METHODS AND RESULTS: We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks.

CONCLUSIONS: In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.

VL - 119 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19204306?dopt=Abstract ER - TY - JOUR T1 - Genomewide association studies of stroke. JF - N Engl J Med Y1 - 2009 A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - DeStefano, Anita L A1 - Aulchenko, Yurii S A1 - Debette, Stephanie A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - van den Herik, Evita G A1 - Bos, Michiel J A1 - Beiser, Alexa A1 - Cushman, Mary A1 - Launer, Lenore J A1 - Shahar, Eyal A1 - Struchalin, Maksim A1 - Du, Yangchun A1 - Glazer, Nicole L A1 - Rosamond, Wayne D A1 - Rivadeneira, Fernando A1 - Kelly-Hayes, Margaret A1 - Lopez, Oscar L A1 - Coresh, Josef A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Heckbert, Susan R A1 - Koudstaal, Peter J A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Kase, Carlos S A1 - Rice, Kenneth A1 - Haritunians, Talin A1 - Roks, Gerwin A1 - de Kort, Paul L M A1 - Taylor, Kent D A1 - de Lau, Lonneke M A1 - Oostra, Ben A A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B A1 - Longstreth, W T A1 - Wolf, Philip A KW - African Continental Ancestry Group KW - Aged KW - Chromosomes, Human, Pair 12 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors KW - Stroke AB -

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

VL - 360 IS - 17 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract ER - TY - JOUR T1 - Hypertension genes and retinal vascular calibre: the Cardiovascular Health Study. JF - J Hum Hypertens Y1 - 2009 A1 - Sun, C A1 - Wang, J J A1 - Islam, F M A1 - Heckbert, S R A1 - Klein, R A1 - Siscovick, D S A1 - Klein, B E K A1 - Wong, T Y KW - African Americans KW - Aged KW - Aged, 80 and over KW - Arterioles KW - Calmodulin-Binding Proteins KW - European Continental Ancestry Group KW - Heterotrimeric GTP-Binding Proteins KW - Humans KW - Hypertension KW - Longitudinal Studies KW - Polymorphism, Single Nucleotide KW - Receptors, Adrenergic, beta-2 KW - Retinal Vessels AB -

We examined the associations of single nucleotide polymorphisms (SNPs) in three candidate hypertension genes, alpha-adducin (ADD1/G460W), beta2-adrenergic receptor (ADRB2/Arg16Gly and Gln27Glu) and G-protein beta3 subunit (GNB3/C825T), with retinal arteriolar calibre (an intermediate marker of chronic hypertension) and venular calibre. Data in 1842 participants (1554 whites and 288 African Americans) aged 69-96 years from the Cardiovascular Health Study with genotype and retinal vascular calibre data were included. A computer-assisted method was used to measure retinal vascular calibre. We analysed four SNPs and multilocus interaction for three genes. All SNPs were in Hardy-Weinberg equilibrium in whites and African Americans. The study had sufficient power to detect 0.5% of the total variance of retinal vascular calibre contributed by each SNP in the total population, except for the GNB3 gene variant. No significant associations between these SNPs in the genes studied and mean retinal arteriolar and venular calibre were found in single-gene or multilocus analysis (for example, age-, gender-, race-adjusted mean retinal arteriolar calibre was similar between participants who were ADD1/460W homozygotes and ADD1/G allele carriers, 166.2 vs 167.7 microm). In conclusion, this study found no evidence of an association of SNPs in candidate hypertension genes studied here with retinal vascular calibre.

VL - 23 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19148102?dopt=Abstract ER - TY - JOUR T1 - Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. JF - Sleep Y1 - 2009 A1 - Phillips, Barbara A1 - Bůzková, Petra A1 - Enright, Paul KW - African Americans KW - Aged KW - Cohort Studies KW - Comorbidity KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Humans KW - Hypertension KW - Male KW - Prospective Studies KW - Risk Factors KW - Sleep Initiation and Maintenance Disorders KW - United States AB -

STUDY OBJECTIVE: We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction.

DESIGN: This is a prospective cohort study over a 6-year period of follow-up.

SETTING: This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland.

PARTICIPANTS: The study analyzed data from 1419 older individuals (baseline mean age 73.4 +/- 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline.

INTERVENTIONS: none.

MEASUREMENTS: We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination.

RESULTS: Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans.

CONCLUSIONS: Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.

VL - 32 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19189780?dopt=Abstract ER - TY - JOUR T1 - Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. JF - PLoS One Y1 - 2009 A1 - Arking, Dan E A1 - Khera, Amit A1 - Xing, Chao A1 - Kao, W H Linda A1 - Post, Wendy A1 - Boerwinkle, Eric A1 - Chakravarti, Aravinda KW - Adaptor Proteins, Signal Transducing KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Heart Diseases KW - Heart Rate KW - Hispanic Americans KW - Humans KW - Linear Models KW - Linkage Disequilibrium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sex Factors KW - Young Adult AB -

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

VL - 4 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19180230?dopt=Abstract ER - TY - JOUR T1 - NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. JF - PLoS Genet Y1 - 2009 A1 - Heard-Costa, Nancy L A1 - Zillikens, M Carola A1 - Monda, Keri L A1 - Johansson, Asa A1 - Harris, Tamara B A1 - Fu, Mao A1 - Haritunians, Talin A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Garcia, Melissa A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Mitchell, Braxton D A1 - McArdle, Patrick F A1 - Shuldiner, Alan R A1 - Bielinski, Suzette J A1 - Boerwinkle, Eric A1 - Brancati, Fred A1 - Demerath, Ellen W A1 - Pankow, James S A1 - Arnold, Alice M A1 - Chen, Yii-Der Ida A1 - Glazer, Nicole L A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Amin, Najaf A1 - Campbell, Harry A1 - Gyllensten, Ulf A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Rudan, Igor A1 - Struchalin, Maksim A1 - Vitart, Veronique A1 - Gao, Xiaoyi A1 - Kraja, Aldi A1 - Province, Michael A A1 - Zhang, Qunyuan A1 - Atwood, Larry D A1 - Dupuis, Josée A1 - Hirschhorn, Joel N A1 - Jaquish, Cashell E A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - White, Charles C A1 - Aulchenko, Yurii S A1 - Estrada, Karol A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Oostra, Ben A A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - North, Kari E KW - Aged KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist Circumference AB -

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract ER - TY - JOUR T1 - Prevalence of hearing loss in Black and White elders: results of the Cardiovascular Health Study. JF - J Speech Lang Hear Res Y1 - 2009 A1 - Pratt, Sheila R A1 - Kuller, Lewis A1 - Talbott, Evelyn O A1 - McHugh-Pemu, Kathleen A1 - Buhari, Alhaji M A1 - Xu, Xiaohui KW - African Americans KW - Aged KW - Aged, 80 and over KW - Aging KW - Auditory Threshold KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Hearing Loss KW - Hearing Tests KW - Humans KW - Male KW - Occupations KW - Prevalence KW - Sex Characteristics KW - Smoking KW - Socioeconomic Factors KW - United States AB -

PURPOSE: The goal of this study was to determine the impact of age, gender, and race on the prevalence and severity of hearing loss in elder adults, aged 72-96 years, after accounting for income, education, smoking, and clinical and subclinical cardiovascular disease. Methods Air-conduction thresholds for standard and extended high-frequency pure-tones were obtained from a cohort of 548 (out of 717) elderly adults (ages 72-96 years) who were recruited during the Year 11 clinical visit (1999-2000) of the Cardiovascular Health Study (CHS) at the Pittsburgh, Pennsylvania site. Participant smoking, income, education, and cardiovascular disease histories were obtained from the CHS database and were included as factors.

RESULTS: Hearing loss was more common and more severe for the participants in their 80s than for those in their 70s-the men more than the women and the White participants more than the Black participants. The inclusion of education, income, smoking, and cardiovascular disease (clinical and subclinical) histories as factors did not substantively impact the overall results.

CONCLUSION: Although the data reported in this article were cross-sectional and a cohort phenomenon might have been operational, they suggested that hearing loss is more substantive in the 8th than the 7th decade of life and that race and gender influence this decline in audition. Given the high prevalence in the aging population and the differences across groups, there is a clear need to understand the nature and causes of hearing loss across various groups in order to improve prevention and develop appropriate interventions.

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

In patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults > or =65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15% to 20% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences.

VL - 103 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19361600?dopt=Abstract ER - TY - JOUR T1 - Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. JF - Nat Genet Y1 - 2009 A1 - Benjamin, Emelia J A1 - Rice, Kenneth M A1 - Arking, Dan E A1 - Pfeufer, Arne A1 - van Noord, Charlotte A1 - Smith, Albert V A1 - Schnabel, Renate B A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Sinner, Moritz F A1 - Dehghan, Abbas A1 - Lubitz, Steven A A1 - D'Agostino, Ralph B A1 - Lumley, Thomas A1 - Ehret, Georg B A1 - Heeringa, Jan A1 - Aspelund, Thor A1 - Newton-Cheh, Christopher A1 - Larson, Martin G A1 - Marciante, Kristin D A1 - Soliman, Elsayed Z A1 - Rivadeneira, Fernando A1 - Wang, Thomas J A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Psaty, Bruce M A1 - Li, Man A1 - Chamberlain, Alanna M A1 - Hofman, Albert A1 - Vasan, Ramachandran S A1 - Harris, Tamara B A1 - Rotter, Jerome I A1 - Kao, W H Linda A1 - Agarwal, Sunil K A1 - Stricker, Bruno H Ch A1 - Wang, Ke A1 - Launer, Lenore J A1 - Smith, Nicholas L A1 - Chakravarti, Aravinda A1 - Uitterlinden, André G A1 - Wolf, Philip A A1 - Sotoodehnia, Nona A1 - Köttgen, Anna A1 - van Duijn, Cornelia M A1 - Meitinger, Thomas A1 - Mueller, Martina A1 - Perz, Siegfried A1 - Steinbeck, Gerhard A1 - Wichmann, H-Erich A1 - Lunetta, Kathryn L A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Witteman, Jacqueline C M KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 16 KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeodomain Proteins KW - Humans KW - Meta-Analysis as Topic KW - Mutation KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results AB -

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

VL - 41 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract ER - TY - JOUR T1 - Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. JF - Nat Genet Y1 - 2010 A1 - Speliotes, Elizabeth K A1 - Willer, Cristen J A1 - Berndt, Sonja I A1 - Monda, Keri L A1 - Thorleifsson, Gudmar A1 - Jackson, Anne U A1 - Lango Allen, Hana A1 - Lindgren, Cecilia M A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Workalemahu, Tsegaselassie A1 - Heid, Iris M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Weedon, Michael N A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Ferreira, Teresa A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Estrada, Karol A1 - Liang, Liming A1 - Nemesh, James A1 - Park, Ju-Hyun A1 - Gustafsson, Stefan A1 - Kilpeläinen, Tuomas O A1 - Yang, Jian A1 - Bouatia-Naji, Nabila A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Raychaudhuri, Soumya A1 - Scherag, Andre A1 - Smith, Albert Vernon A1 - Welch, Ryan A1 - Zhao, Jing Hua A1 - Aben, Katja K A1 - Absher, Devin M A1 - Amin, Najaf A1 - Dixon, Anna L A1 - Fisher, Eva A1 - Glazer, Nicole L A1 - Goddard, Michael E A1 - Heard-Costa, Nancy L A1 - Hoesel, Volker A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Lamina, Claudia A1 - Li, Shengxu A1 - Moffatt, Miriam F A1 - Myers, Richard H A1 - Narisu, Narisu A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan P A1 - van Wingerden, Sophie A1 - Watanabe, Richard M A1 - White, Charles C A1 - Wiklund, Fredrik A1 - Barlassina, Christina A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Prokopenko, Inga A1 - Shi, Jianxin A1 - Thiering, Elisabeth A1 - Alavere, Helene A1 - Alibrandi, Maria T S A1 - Almgren, Peter A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Atwood, Larry D A1 - Balkau, Beverley A1 - Balmforth, Anthony J A1 - Bennett, Amanda J A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Biebermann, Heike A1 - Blakemore, Alexandra I F A1 - Boes, Tanja A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Brown, Morris J A1 - Buchanan, Thomas A A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Cavalcanti-Proença, Christine A1 - Chen, Yii-Der Ida A1 - Chen, Chih-Mei A1 - Chines, Peter S A1 - Clarke, Robert A1 - Coin, Lachlan A1 - Connell, John A1 - Day, Ian N M A1 - den Heijer, Martin A1 - Duan, Jubao A1 - Ebrahim, Shah A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eiriksdottir, Gudny A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Facheris, Maurizio F A1 - Felix, Stephan B A1 - Fischer-Posovszky, Pamela A1 - Folsom, Aaron R A1 - Friedrich, Nele A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Gejman, Pablo V A1 - Geus, Eco J C A1 - Gieger, Christian A1 - Gjesing, Anette P A1 - Goel, Anuj A1 - Goyette, Philippe A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Greenawalt, Danielle M A1 - Groves, Christopher J A1 - Gudnason, Vilmundur A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hall, Alistair S A1 - Havulinna, Aki S A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hinney, Anke A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jacobs, Kevin B A1 - Jarick, Ivonne A1 - Jewell, Elizabeth A1 - John, Ulrich A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kajantie, Eero A1 - Kaplan, Lee M A1 - Kathiresan, Sekar A1 - Kettunen, Johannes A1 - Kinnunen, Leena A1 - Knowles, Joshua W A1 - Kolcic, Ivana A1 - König, Inke R A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kuusisto, Johanna A1 - Kraft, Peter A1 - Kvaløy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lanzani, Chiara A1 - Launer, Lenore J A1 - Lecoeur, Cécile A1 - Lehtimäki, Terho A1 - Lettre, Guillaume A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - Manunta, Paolo A1 - Marek, Diana A1 - Marre, Michel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - McKnight, Barbara A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Meyre, David A1 - Midthjell, Kristian A1 - Montgomery, Grant W A1 - Morken, Mario A A1 - Morris, Andrew P A1 - Mulic, Rosanda A1 - Ngwa, Julius S A1 - Nelis, Mari A1 - Neville, Matt J A1 - Nyholt, Dale R A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Ong, Ken K A1 - Oostra, Ben A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Perola, Markus A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Rafelt, Suzanne A1 - Raitakari, Olli A1 - Rayner, Nigel W A1 - Ridderstråle, Martin A1 - Rief, Winfried A1 - Ruokonen, Aimo A1 - Robertson, Neil R A1 - Rzehak, Peter A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sandhu, Manjinder S A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Savolainen, Markku J A1 - Scherag, Susann A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Silander, Kaisa A1 - Sinisalo, Juha A1 - Siscovick, David S A1 - Smit, Jan H A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Stephens, Jonathan A1 - Surakka, Ida A1 - Swift, Amy J A1 - Tammesoo, Mari-Liis A1 - Tardif, Jean-Claude A1 - Teder-Laving, Maris A1 - Teslovich, Tanya M A1 - Thompson, John R A1 - Thomson, Brian A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Viikari, Jorma A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogel, Carla I G A1 - Voight, Benjamin F A1 - Waite, Lindsay L A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wiegand, Susanna A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Witteman, Jacqueline C A1 - Xu, Jianfeng A1 - Zhang, Qunyuan A1 - Zgaga, Lina A1 - Ziegler, Andreas A1 - Zitting, Paavo A1 - Beilby, John P A1 - Farooqi, I Sadaf A1 - Hebebrand, Johannes A1 - Huikuri, Heikki V A1 - James, Alan L A1 - Kähönen, Mika A1 - Levinson, Douglas F A1 - Macciardi, Fabio A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Beckmann, Jacques S A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Collins, Francis S A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Erdmann, Jeanette A1 - Froguel, Philippe A1 - Grönberg, Henrik A1 - Gyllensten, Ulf A1 - Hall, Per A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayes, Richard B A1 - Heinrich, Joachim A1 - Hu, Frank B A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Kaprio, Jaakko A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Kiemeney, Lambertus A A1 - Krude, Heiko A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Metspalu, Andres A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Pedersen, Oluf A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Reinehr, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Spector, Timothy D A1 - Tuomilehto, Jaakko A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Valle, Timo T A1 - Wabitsch, Martin A1 - Waeber, Gérard A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Chatterjee, Nilanjan A1 - McCarroll, Steven A A1 - Purcell, Shaun A1 - Schadt, Eric E A1 - Visscher, Peter M A1 - Assimes, Themistocles L A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Frayling, Timothy M A1 - Thorsteinsdottir, Unnur A1 - Abecasis, Goncalo R A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Stefansson, Kari A1 - North, Kari E A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Ingelsson, Erik A1 - Loos, Ruth J F KW - Body Height KW - Body Mass Index KW - Body Size KW - Body Weight KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

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

BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.

CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20445134?dopt=Abstract ER - TY - JOUR T1 - Biological, clinical and population relevance of 95 loci for blood lipids. JF - Nature Y1 - 2010 A1 - Teslovich, Tanya M A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Ripatti, Samuli A1 - Chasman, Daniel I A1 - Willer, Cristen J A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Isaacs, Aaron A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - Feitosa, Mary F A1 - Chambers, John A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Johnson, Toby A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Li, Mingyao A1 - Shin Cho, Yoon A1 - Jin Go, Min A1 - Jin Kim, Young A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Twee-Hee Ong, Rick A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Song, Kijoung A1 - Hua Zhao, Jing A1 - Yuan, Xin A1 - Luan, Jian'an A1 - Lamina, Claudia A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Wright, Alan F A1 - Witteman, Jacqueline C M A1 - Wilson, James F A1 - Willemsen, Gonneke A1 - Wichmann, H-Erich A1 - Whitfield, John B A1 - Waterworth, Dawn M A1 - Wareham, Nicholas J A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Voight, Benjamin F A1 - Vitart, Veronique A1 - Uitterlinden, André G A1 - Uda, Manuela A1 - Tuomilehto, Jaakko A1 - Thompson, John R A1 - Tanaka, Toshiko A1 - Surakka, Ida A1 - Stringham, Heather M A1 - Spector, Tim D A1 - Soranzo, Nicole A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Silander, Kaisa A1 - Sijbrands, Eric J G A1 - Scuteri, Angelo A1 - Scott, James A1 - Schlessinger, David A1 - Sanna, Serena A1 - Salomaa, Veikko A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Ruokonen, Aimo A1 - Rudan, Igor A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Psaty, Bruce M A1 - Pramstaller, Peter P A1 - Pichler, Irene A1 - Perola, Markus A1 - Penninx, Brenda W J H A1 - Pedersen, Nancy L A1 - Pattaro, Cristian A1 - Parker, Alex N A1 - Paré, Guillaume A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - Meitinger, Thomas A1 - McPherson, Ruth A1 - McCarthy, Mark I A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Mangino, Massimo A1 - Magnusson, Patrik K E A1 - Lucas, Gavin A1 - Luben, Robert A1 - Loos, Ruth J F A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - Kronenberg, Florian A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaprio, Jaakko A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Jarvelin, Marjo-Riitta A1 - Janssens, A Cecile J W A1 - Ingelsson, Erik A1 - Igl, Wilmar A1 - Kees Hovingh, G A1 - Hottenga, Jouke-Jan A1 - Hofman, Albert A1 - Hicks, Andrew A A1 - Hengstenberg, Christian A1 - Heid, Iris M A1 - Hayward, Caroline A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Gyllensten, Ulf A1 - Guiducci, Candace A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Gieger, Christian A1 - Freimer, Nelson B A1 - Ferrucci, Luigi A1 - Erdmann, Jeanette A1 - Elliott, Paul A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Geus, Eco J C A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Collins, Francis S A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Campbell, Harry A1 - Burtt, Noel P A1 - Bonnycastle, Lori L A1 - Boomsma, Dorret I A1 - Boekholdt, S Matthijs A1 - Bergman, Richard N A1 - Barroso, Inês A1 - Bandinelli, Stefania A1 - Ballantyne, Christie M A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Altshuler, David A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Adair, Linda S A1 - Taylor, Herman A A1 - Borecki, Ingrid B A1 - Gabriel, Stacey B A1 - Wilson, James G A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Mohlke, Karen L A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Strachan, David P A1 - Mooser, Vincent A1 - Stefansson, Kari A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Kathiresan, Sekar KW - African Americans KW - Animals KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Male KW - Mice KW - N-Acetylgalactosaminyltransferases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Protein Phosphatase 1 KW - Reproducibility of Results KW - Triglycerides AB -

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

VL - 466 IS - 7307 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract ER - TY - JOUR T1 - Cancer linked to Alzheimer disease but not vascular dementia. JF - Neurology Y1 - 2010 A1 - Roe, C M A1 - Fitzpatrick, A L A1 - Xiong, C A1 - Sieh, W A1 - Kuller, L A1 - Miller, J P A1 - Williams, M M A1 - Kopan, R A1 - Behrens, M I A1 - Morris, J C KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Cohort Studies KW - Dementia, Vascular KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Hospitalization KW - Humans KW - Male KW - Neoplasms KW - Nerve Degeneration KW - Parkinson Disease KW - Prevalence KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors AB -

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).

METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.

RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.

CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

VL - 74 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20032288?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association resource (CARe): design, methods, and proof of concept. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Musunuru, Kiran A1 - Lettre, Guillaume A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Pirruccello, James P A1 - Ejebe, Kenechi G A1 - Keating, Brendan J A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Lapchyk, Nina A1 - Crenshaw, Andrew A1 - Ziaugra, Liuda A1 - Rachupka, Anthony A1 - Benjamin, Emelia J A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Hirschhorn, Joel N A1 - Newton-Cheh, Christopher A1 - Nizzari, Marcia M A1 - Paltoo, Dina N A1 - Papanicolaou, George J A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Kathiresan, Sekar A1 - Fabsitz, Richard R A1 - Boerwinkle, Eric A1 - Gabriel, Stacey B KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Databases, Genetic KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genotype KW - Humans KW - Phenotype KW - Pilot Projects KW - Polymorphism, Single Nucleotide KW - Research Design KW - Triglycerides AB -

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract ER - TY - JOUR T1 - Common genetic determinants of vitamin D insufficiency: a genome-wide association study. JF - Lancet Y1 - 2010 A1 - Wang, Thomas J A1 - Zhang, Feng A1 - Richards, J Brent A1 - Kestenbaum, Bryan A1 - van Meurs, Joyce B A1 - Berry, Diane A1 - Kiel, Douglas P A1 - Streeten, Elizabeth A A1 - Ohlsson, Claes A1 - Koller, Daniel L A1 - Peltonen, Leena A1 - Cooper, Jason D A1 - O'Reilly, Paul F A1 - Houston, Denise K A1 - Glazer, Nicole L A1 - Vandenput, Liesbeth A1 - Peacock, Munro A1 - Shi, Julia A1 - Rivadeneira, Fernando A1 - McCarthy, Mark I A1 - Anneli, Pouta A1 - de Boer, Ian H A1 - Mangino, Massimo A1 - Kato, Bernet A1 - Smyth, Deborah J A1 - Booth, Sarah L A1 - Jacques, Paul F A1 - Burke, Greg L A1 - Goodarzi, Mark A1 - Cheung, Ching-Lung A1 - Wolf, Myles A1 - Rice, Kenneth A1 - Goltzman, David A1 - Hidiroglou, Nick A1 - Ladouceur, Martin A1 - Wareham, Nicholas J A1 - Hocking, Lynne J A1 - Hart, Deborah A1 - Arden, Nigel K A1 - Cooper, Cyrus A1 - Malik, Suneil A1 - Fraser, William D A1 - Hartikainen, Anna-Liisa A1 - Zhai, Guangju A1 - Macdonald, Helen M A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Reid, David M A1 - Hakim, Alan A1 - Dennison, Elaine A1 - Liu, Yongmei A1 - Power, Chris A1 - Stevens, Helen E A1 - Jaana, Laitinen A1 - Vasan, Ramachandran S A1 - Soranzo, Nicole A1 - Bojunga, Jörg A1 - Psaty, Bruce M A1 - Lorentzon, Mattias A1 - Foroud, Tatiana A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Jansson, John-Olov A1 - Cauley, Jane A A1 - Uitterlinden, André G A1 - Gibson, Quince A1 - Jarvelin, Marjo-Riitta A1 - Karasik, David A1 - Siscovick, David S A1 - Econs, Michael J A1 - Kritchevsky, Stephen B A1 - Florez, Jose C A1 - Todd, John A A1 - Dupuis, Josée A1 - Hyppönen, Elina A1 - Spector, Timothy D KW - Canada KW - Chromosomes, Human, Pair 11 KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - Dietary Supplements KW - Europe KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoassay KW - International Cooperation KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide KW - Seasons KW - United States KW - Vitamin D KW - Vitamin D Deficiency AB -

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

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

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

VL - 21 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract ER - TY - JOUR T1 - CRP gene variation and risk of community-acquired pneumonia. JF - Respirology Y1 - 2010 A1 - Mukamal, Kenneth J A1 - Pai, Jennifer K A1 - O'Meara, Ellen S A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Newman, Anne B A1 - Yende, Sachin A1 - Curhan, Gary C A1 - Siscovick, David S A1 - Rimm, Eric B KW - African Americans KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - C-Reactive Protein KW - Cohort Studies KW - Community-Acquired Infections KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Pneumonia KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Smoking AB -

BACKGROUND AND OBJECTIVE: CRP has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain.

METHODS: We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study, a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study who self-reported pneumonia on biennial questionnaires.

RESULTS: There were 581 (507 white and 74 black) Cardiovascular Health Study participants with incident hospitalizations for pneumonia. No single nucleotide polymorphism or haplotypes were associated with risk among white Cardiovascular Health Study participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval: 0.3-0.9) and with higher CRP levels. In Health Professionals Follow-up Study, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels.

CONCLUSIONS: Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.

VL - 15 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19947988?dopt=Abstract ER - TY - JOUR T1 - European ancestry as a risk factor for atrial fibrillation in African Americans. JF - Circulation Y1 - 2010 A1 - Marcus, Gregory M A1 - Alonso, Alvaro A1 - Peralta, Carmen A A1 - Lettre, Guillaume A1 - Vittinghoff, Eric A1 - Lubitz, Steven A A1 - Fox, Ervin R A1 - Levitzky, Yamini S A1 - Mehra, Reena A1 - Kerr, Kathleen F A1 - Deo, Rajat A1 - Sotoodehnia, Nona A1 - Akylbekova, Meggie A1 - Ellinor, Patrick T A1 - Paltoo, Dina N A1 - Soliman, Elsayed Z A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Atrial Fibrillation KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.

METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.

CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.

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

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

VL - 6 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. JF - PLoS Genet Y1 - 2010 A1 - Meyer, Tamra E A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Glazer, Nicole L A1 - Smith, Albert V A1 - van Rooij, Frank J A A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Felix, Janine F A1 - Leak, Tennille S A1 - Harris, Tamara B A1 - Yang, Qiong A1 - Dehghan, Abbas A1 - Aspelund, Thor A1 - Katz, Ronit A1 - Homuth, Georg A1 - Kocher, Thomas A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Gieger, Christian A1 - Prucha, Hanna A1 - Pfeufer, Arne A1 - Meitinger, Thomas A1 - Coresh, Josef A1 - Hofman, Albert A1 - Sarnak, Mark J A1 - Chen, Yii-Der Ida A1 - Uitterlinden, André G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Magnesium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Potassium KW - Sodium AB -

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

VL - 6 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract ER - TY - JOUR T1 - Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Morrison, Alanna C A1 - Felix, Janine F A1 - Cupples, L Adrienne A1 - Glazer, Nicole L A1 - Loehr, Laura R A1 - Dehghan, Abbas A1 - Demissie, Serkalem A1 - Bis, Joshua C A1 - Rosamond, Wayne D A1 - Aulchenko, Yurii S A1 - Wang, Ying A A1 - Haritunians, Talin A1 - Folsom, Aaron R A1 - Rivadeneira, Fernando A1 - Benjamin, Emelia J A1 - Lumley, Thomas A1 - Couper, David A1 - Stricker, Bruno H A1 - O'Donnell, Christopher J A1 - Rice, Kenneth M A1 - Chang, Patricia P A1 - Hofman, Albert A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Fox, Ervin R A1 - Uitterlinden, André G A1 - Wang, Thomas J A1 - Psaty, Bruce M A1 - Willerson, James T A1 - van Duijn, Cornelia M A1 - Boerwinkle, Eric A1 - Witteman, Jacqueline C M A1 - Vasan, Ramachandran S A1 - Smith, Nicholas L KW - African Americans KW - Aged KW - Aged, 80 and over KW - Chemokines KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart Failure KW - Humans KW - Introns KW - Male KW - MARVEL Domain-Containing Proteins KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract ER - TY - JOUR T1 - Independent susceptibility markers for atrial fibrillation on chromosome 4q25. JF - Circulation Y1 - 2010 A1 - Lubitz, Steven A A1 - Sinner, Moritz F A1 - Lunetta, Kathryn L A1 - Makino, Seiko A1 - Pfeufer, Arne A1 - Rahman, Rosanna A1 - Veltman, Caroline E A1 - Barnard, John A1 - Bis, Joshua C A1 - Danik, Stephan P A1 - Sonni, Akshata A1 - Shea, Marisa A A1 - Del Monte, Federica A1 - Perz, Siegfried A1 - Müller, Martina A1 - Peters, Annette A1 - Greenberg, Steven M A1 - Furie, Karen L A1 - van Noord, Charlotte A1 - Boerwinkle, Eric A1 - Stricker, Bruno H C A1 - Witteman, Jacqueline A1 - Smith, Jonathan D A1 - Chung, Mina K A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Rosand, Jonathan A1 - Arking, Dan E A1 - Alonso, Alvaro A1 - Kääb, Stefan A1 - Ellinor, Patrick T KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Chromosome Mapping KW - Chromosomes, Human, Pair 4 KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.

METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.

CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

VL - 122 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20733104?dopt=Abstract ER - TY - JOUR T1 - Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. JF - Diabetes Care Y1 - 2010 A1 - Nettleton, Jennifer A A1 - McKeown, Nicola M A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Hivert, Marie-France A1 - Ngwa, Julius A1 - van Rooij, Frank J A A1 - Sonestedt, Emily A1 - Wojczynski, Mary K A1 - Ye, Zheng A1 - Tanaka, Tosh A1 - Garcia, Melissa A1 - Anderson, Jennifer S A1 - Follis, Jack L A1 - Djoussé, Luc A1 - Mukamal, Kenneth A1 - Papoutsakis, Constantina A1 - Mozaffarian, Dariush A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Bennett, Amanda J A1 - Borecki, Ingrid B A1 - Feitosa, Mary F A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Harris, Tamara A1 - Hofman, Albert A1 - Houston, Denise K A1 - Hu, Frank B A1 - Johansson, Ingegerd A1 - Kritchevsky, Stephen B A1 - Langenberg, Claudia A1 - Launer, Lenore A1 - Liu, Yongmei A1 - Loos, Ruth J A1 - Nalls, Michael A1 - Orho-Melander, Marju A1 - Renstrom, Frida A1 - Rice, Kenneth A1 - Riserus, Ulf A1 - Rolandsson, Olov A1 - Rotter, Jerome I A1 - Saylor, Georgia A1 - Sijbrands, Eric J G A1 - Sjogren, Per A1 - Smith, Albert A1 - Steingrímsdóttir, Laufey A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Prokopenko, Inga A1 - Pankow, James S A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Witteman, Jacqueline C M A1 - Dupuis, Josée A1 - Dedoussis, George V A1 - Ordovas, Jose M A1 - Ingelsson, Erik A1 - Cupples, L Adrienne A1 - Siscovick, David S A1 - Franks, Paul W A1 - Meigs, James B KW - Adult KW - Aged KW - Blood Glucose KW - Edible Grain KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.

RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.

RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.

CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20693352?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. JF - Hum Mol Genet Y1 - 2010 A1 - Barbalic, Maja A1 - Dupuis, Josée A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - Hoogeveen, Ron C A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Bretler, Monique A1 - Smith, Nicholas L A1 - Peters, Annette A1 - Lu, Chen A1 - Tracy, Russell P A1 - Aleksic, Nena A1 - Heeriga, Jan A1 - Keaney, John F A1 - Rice, Kenneth A1 - Lip, Gregory Y H A1 - Vasan, Ramachandran S A1 - Glazer, Nicole L A1 - Larson, Martin G A1 - Uitterlinden, André G A1 - Yamamoto, Jennifer A1 - Durda, Peter A1 - Haritunians, Talin A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Hofman, Albert A1 - Koenig, Wolfgang A1 - Jenny, Nancy S A1 - Witteman, Jacqueline C A1 - Ballantyne, Christie A1 - Benjamin, Emelia J KW - ABO Blood-Group System KW - Blood Platelets KW - Enzyme-Linked Immunosorbent Assay KW - European Continental Ancestry Group KW - Fluorescence KW - Genome-Wide Association Study KW - Humans KW - Intercellular Adhesion Molecule-1 KW - P-Selectin AB -

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

VL - 19 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract ER - TY - JOUR T1 - Sleep disturbances, quality of life, and ethnicity: the Sleep Heart Health Study. JF - J Clin Sleep Med Y1 - 2010 A1 - Baldwin, Carol M A1 - Ervin, Ann-Margret A1 - Mays, Mary Z A1 - Robbins, John A1 - Shafazand, Shirin A1 - Walsleben, Joyce A1 - Weaver, Terri KW - African Americans KW - Cohort Studies KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Health Status KW - Heart Diseases KW - Hispanic Americans KW - Humans KW - Longitudinal Studies KW - Male KW - Mental Health KW - Middle Aged KW - Polysomnography KW - Prevalence KW - Quality of Life KW - Sleep Apnea, Obstructive KW - Sleep Initiation and Maintenance Disorders KW - Sleep Wake Disorders KW - Snoring KW - Surveys and Questionnaires KW - United States AB -

STUDY OBJECTIVES: To compare health-related quality of life (HR-QOL) across subgroups defined by sleep disturbances and ethnicity.

METHODS: Men (47%) and women (53%) Sleep Heart Health Study participants age 40 and older (N = 5237) underwent overnight polysomnography and completed self-report questionnaires on symptoms of sleep disturbances. The physical and mental composite scales (PCS and MCS) of the Medical Outcomes Study 36-item short form survey assessed HR-QOL and were compared to sleep data.

RESULTS: Participants self-identified as Caucasian/White (n = 4482, 86%), African American/Black (n = 490, 9%), or Hispanic/Mexican American (n = 265, 5%). The prevalence of obstructive sleep apnea (OSA) was 17%, frequent snoring was 34%, difficulty initiating or maintaining sleep (DIMS; insomnia symptoms) was 30%, and excessive daytime sleepiness (EDS) was 25%. African American participants with frequent snoring, insomnia symptoms, or EDS had significantly poorer physical health compared to Caucasians (p < 0.001). Hispanics with frequent snoring, insomnia symptoms, or EDS had significantly poorer mental health than Caucasian participants (p <0.001). Neither PCS nor MCS scores differed significantly across ethnic subgroups for participants with moderate to severe OSA (respiratory disturbance index > 15, 4% desaturation).

CONCLUSIONS: Across ethnic/racial subgroups, sleep disturbances are associated with worse physical and better mental HR-QOL than the U.S. norm, but this relationship may be moderated by comorbid health conditions. This study replicates and extends prior research indicating differences among minority and non-minority participants and highlights the need for future studies of sleep disturbances with larger samples of minorities that control for comorbid health conditions.

VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20411696?dopt=Abstract ER - TY - JOUR T1 - Validation of an atrial fibrillation risk algorithm in whites and African Americans. JF - Arch Intern Med Y1 - 2010 A1 - Schnabel, Renate B A1 - Aspelund, Thor A1 - Li, Guo A1 - Sullivan, Lisa M A1 - Suchy-Dicey, Astrid A1 - Harris, Tamara B A1 - Pencina, Michael J A1 - D'Agostino, Ralph B A1 - Levy, Daniel A1 - Kannel, William B A1 - Wang, Thomas J A1 - Kronmal, Richard A A1 - Wolf, Philip A A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Benjamin, Emelia J A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Atrial Fibrillation KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Electrocardiography KW - Europe KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Hypertension KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Risk Factors KW - Sex Factors KW - Systole KW - United States AB -

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.

CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

VL - 170 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21098350?dopt=Abstract ER - TY - JOUR T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. JF - PLoS Genet Y1 - 2011 A1 - Böger, Carsten A A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M A1 - Kutalik, Zoltán A1 - Wichmann, H-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Beckmann, Jacques S A1 - Krämer, Bernhard K A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Kao, W H KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Chronic Disease KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Association Studies KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptor, Epidermal Growth Factor KW - Uromodulin AB -

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21980298?dopt=Abstract ER - TY - JOUR T1 - The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study. JF - Exp Gerontol Y1 - 2011 A1 - Benke, K S A1 - Carlson, M C A1 - Doan, B Q A1 - Walston, J D A1 - Xue, Q L A1 - Reiner, A P A1 - Fried, L P A1 - Arking, D E A1 - Chakravarti, A A1 - Fallin, M D KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cognition KW - Cognition Disorders KW - Dementia KW - Educational Status KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-1alpha KW - Interleukin-1beta KW - Linkage Disequilibrium KW - Longitudinal Studies KW - Male KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - United States AB -

The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer's, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.

VL - 46 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21968104?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. JF - Hum Mol Genet Y1 - 2011 A1 - Fox, Ervin R A1 - Young, J Hunter A1 - Li, Yali A1 - Dreisbach, Albert W A1 - Keating, Brendan J A1 - Musani, Solomon K A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Ganesh, Santhi A1 - Kutlar, Abdullah A1 - Ramachandran, Vasan S A1 - Polak, Josef F A1 - Fabsitz, Richard R A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Redline, Susan A1 - Adeyemo, Adebowale A1 - Hirschorn, Joel N A1 - Sun, Yan V A1 - Wyatt, Sharon B A1 - Penman, Alan D A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Townsend, Raymond R A1 - Doumatey, Ayo P A1 - Tayo, Bamidele O A1 - Mosley, Thomas H A1 - Lyon, Helen N A1 - Kang, Sun J A1 - Rotimi, Charles N A1 - Cooper, Richard S A1 - Franceschini, Nora A1 - Curb, J David A1 - Martin, Lisa W A1 - Eaton, Charles B A1 - Kardia, Sharon L R A1 - Taylor, Herman A A1 - Caulfield, Mark J A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Levy, Daniel KW - Adult KW - African Americans KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

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

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

VL - 117 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20978265?dopt=Abstract ER - TY - JOUR T1 - The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study. JF - BMC Cardiovasc Disord Y1 - 2011 A1 - Shiffman, Dov A1 - O'Meara, Ellen S A1 - Rowland, Charles M A1 - Louie, Judy Z A1 - Cushman, Mary A1 - Tracy, Russell P A1 - Devlin, James J A1 - Psaty, Bruce M KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Case-Control Studies KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Variation KW - Humans KW - Kinesin KW - Male KW - Myocardial Infarction KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older.

METHODS: Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI).

RESULTS: Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24).

CONCLUSIONS: While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.

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

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium. JF - Hum Mol Genet Y1 - 2011 A1 - Taylor, Kira C A1 - Lange, Leslie A A1 - Zabaneh, Delilah A1 - Lange, Ethan A1 - Keating, Brendan J A1 - Tang, Weihong A1 - Smith, Nicholas L A1 - Delaney, Joseph A A1 - Kumari, Meena A1 - Hingorani, Aroon A1 - North, Kari E A1 - Kivimaki, Mika A1 - Tracy, Russell P A1 - O'Donnell, Christopher J A1 - Folsom, Aaron R A1 - Green, David A1 - Humphries, Steve E A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Factor VII KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.

VL - 20 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21676895?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of fibrin D-dimer levels in healthy adults. JF - Circulation Y1 - 2011 A1 - Smith, Nicholas L A1 - Huffman, Jennifer E A1 - Strachan, David P A1 - Huang, Jie A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Shin, So-Youn A1 - Baumert, Jens A1 - Vitart, Veronique A1 - Bis, Joshua C A1 - Wild, Sarah H A1 - Rumley, Ann A1 - Yang, Qiong A1 - Uitterlinden, André G A1 - Stott, David J A1 - Davies, Gail A1 - Carter, Angela M A1 - Thorand, Barbara A1 - Polasek, Ozren A1 - McKnight, Barbara A1 - Campbell, Harry A1 - Rudnicka, Alicja R A1 - Chen, Ming-Huei A1 - Buckley, Brendan M A1 - Harris, Sarah E A1 - Peters, Annette A1 - Pulanic, Drazen A1 - Lumley, Thomas A1 - de Craen, Anton J M A1 - Liewald, David C A1 - Gieger, Christian A1 - Campbell, Susan A1 - Ford, Ian A1 - Gow, Alan J A1 - Luciano, Michelle A1 - Porteous, David J A1 - Guo, Xiuqing A1 - Sattar, Naveed A1 - Tenesa, Albert A1 - Cushman, Mary A1 - Slagboom, P Eline A1 - Visscher, Peter M A1 - Spector, Tim D A1 - Illig, Thomas A1 - Rudan, Igor A1 - Bovill, Edwin G A1 - Wright, Alan F A1 - McArdle, Wendy L A1 - Tofler, Geoffrey A1 - Hofman, Albert A1 - Westendorp, Rudi G J A1 - Starr, John M A1 - Grant, Peter J A1 - Karakas, Mahir A1 - Hastie, Nicholas D A1 - Psaty, Bruce M A1 - Wilson, James F A1 - Lowe, Gordon D O A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Jukema, J Wouter A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Koenig, Wolfgang A1 - Hayward, Caroline KW - Adult KW - Aged KW - Blood Coagulation KW - European Continental Ancestry Group KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Testing KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Reference Values KW - Thromboplastin AB -

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

VL - 123 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. JF - Nat Genet Y1 - 2011 A1 - Soler Artigas, Maria A1 - Loth, Daan W A1 - Wain, Louise V A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Tang, Wenbo A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Smith, Albert Vernon A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Jackson, Catherine M A1 - Evans, David M A1 - Cadby, Gemma A1 - Fornage, Myriam A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Johnson, Toby A1 - Aldrich, Melinda C A1 - Aspelund, Thor A1 - Barroso, Inês A1 - Campbell, Harry A1 - Cassano, Patricia A A1 - Couper, David J A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Gislason, Gauti Kjartan A1 - Grkovic, Ivica A1 - Hammond, Christopher J A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Ramasamy, Adaikalavan A1 - Heckbert, Susan R A1 - Heliövaara, Markku A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - James, Alan L A1 - Jankovic, Stipan A1 - Joubert, Bonnie R A1 - Karrasch, Stefan A1 - Klopp, Norman A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Launer, Lenore J A1 - Liu, Yongmei A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lumley, Thomas A1 - Al Balushi, Khalid A A1 - Ang, Wei Q A1 - Barr, R Graham A1 - Beilby, John A1 - Blakey, John D A1 - Boban, Mladen A1 - Boraska, Vesna A1 - Brisman, Jonas A1 - Britton, John R A1 - Brusselle, Guy G A1 - Cooper, Cyrus A1 - Curjuric, Ivan A1 - Dahgam, Santosh A1 - Deary, Ian J A1 - Ebrahim, Shah A1 - Eijgelsheim, Mark A1 - Francks, Clyde A1 - Gaysina, Darya A1 - Granell, Raquel A1 - Gu, Xiangjun A1 - Hankinson, John L A1 - Hardy, Rebecca A1 - Harris, Sarah E A1 - Henderson, John A1 - Henry, Amanda A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Holt, Patrick G A1 - Hui, Jennie A1 - Hunter, Michael L A1 - Imboden, Medea A1 - Jameson, Karen A A1 - Kerr, Shona M A1 - Kolcic, Ivana A1 - Kronenberg, Florian A1 - Liu, Jason Z A1 - Marchini, Jonathan A1 - McKeever, Tricia A1 - Morris, Andrew D A1 - Olin, Anna-Carin A1 - Porteous, David J A1 - Postma, Dirkje S A1 - Rich, Stephen S A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Sayer, Avan Aihie A1 - Sayers, Ian A1 - Sly, Peter D A1 - Smith, George Davey A1 - Sood, Akshay A1 - Starr, John M A1 - Uitterlinden, André G A1 - Vonk, Judith M A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Wong, Andrew A1 - Mangino, Massimo A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - North, Kari E A1 - Omenaas, Ernst A1 - Palmer, Lyle J A1 - Pietiläinen, Kirsi H A1 - Pin, Isabelle A1 - Pola Sbreve Ek, Ozren A1 - Pouta, Anneli A1 - Psaty, Bruce M A1 - Hartikainen, Anna-Liisa A1 - Rantanen, Taina A1 - Ripatti, Samuli A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rudnicka, Alicja R A1 - Schulz, Holger A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Warrington, Nicole M A1 - Wichmann, H-Erich A1 - Wild, Sarah H A1 - Wilk, Jemma B A1 - Wjst, Matthias A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Pennell, Craig E A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Holloway, John W A1 - Boezen, H Marike A1 - Lawlor, Debbie A A1 - Morris, Richard W A1 - Probst-Hensch, Nicole A1 - Kaprio, Jaakko A1 - Wilson, James F A1 - Hayward, Caroline A1 - Kähönen, Mika A1 - Heinrich, Joachim A1 - Musk, Arthur W A1 - Jarvis, Deborah L A1 - Gläser, Sven A1 - Jarvelin, Marjo-Riitta A1 - Ch Stricker, Bruno H A1 - Elliott, Paul A1 - O'Connor, George T A1 - Strachan, David P A1 - London, Stephanie J A1 - Hall, Ian P A1 - Gudnason, Vilmundur A1 - Tobin, Martin D KW - Child KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests AB -

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

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

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

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

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

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

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

VL - 20 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract ER - TY - JOUR T1 - Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. JF - PLoS Genet Y1 - 2011 A1 - Arking, Dan E A1 - Junttila, M Juhani A1 - Goyette, Philippe A1 - Huertas-Vazquez, Adriana A1 - Eijgelsheim, Mark A1 - Blom, Marieke T A1 - Newton-Cheh, Christopher A1 - Reinier, Kyndaron A1 - Teodorescu, Carmen A1 - Uy-Evanado, Audrey A1 - Carter-Monroe, Naima A1 - Kaikkonen, Kari S A1 - Kortelainen, Marja-Leena A1 - Boucher, Gabrielle A1 - Lagacé, Caroline A1 - Moes, Anna A1 - Zhao, XiaoQing A1 - Kolodgie, Frank A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Uitterlinden, André G A1 - Marsman, Roos F A1 - Pazoki, Raha A1 - Bardai, Abdennasser A1 - Koster, Rudolph W A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Bhatnagar, Pallav A1 - Post, Wendy A1 - Hilton, Gina A1 - Prineas, Ronald J A1 - Li, Man A1 - Köttgen, Anna A1 - Ehret, Georg A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Kao, W H Linda A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Greg L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Cupples, L Adrienne A1 - Jui, Jonathan A1 - Gunson, Karen A1 - Kesaniemi, Y Antero A1 - Wilde, Arthur A M A1 - Tardif, Jean-Claude A1 - O'Donnell, Christopher J A1 - Bezzina, Connie R A1 - Virmani, Renu A1 - Stricker, Bruno H C H A1 - Tan, Hanno L A1 - Albert, Christine M A1 - Chakravarti, Aravinda A1 - Rioux, John D A1 - Huikuri, Heikki V A1 - Chugh, Sumeet S KW - Adult KW - Aged KW - Alleles KW - Chromosomes, Human, Pair 2 KW - Death, Sudden, Cardiac KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Contraction KW - Polymorphism, Single Nucleotide AB -

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738491?dopt=Abstract ER - TY - JOUR T1 - Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Schnabel, Renate B A1 - Kerr, Kathleen F A1 - Lubitz, Steven A A1 - Alkylbekova, Ermeg L A1 - Marcus, Gregory M A1 - Sinner, Moritz F A1 - Magnani, Jared W A1 - Wolf, Philip A A1 - Deo, Rajat A1 - Lloyd-Jones, Donald M A1 - Lunetta, Kathryn L A1 - Mehra, Reena A1 - Levy, Daniel A1 - Fox, Ervin R A1 - Arking, Dan E A1 - Mosley, Thomas H A1 - Müller-Nurasyid, Martina A1 - Young, Taylor R A1 - Wichmann, H-Erich A1 - Seshadri, Sudha A1 - Farlow, Deborah N A1 - Rotter, Jerome I A1 - Soliman, Elsayed Z A1 - Glazer, Nicole L A1 - Wilson, James G A1 - Breteler, Monique M B A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Alleles KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. JF - Nat Genet Y1 - 2011 A1 - Bis, Joshua C A1 - Kavousi, Maryam A1 - Franceschini, Nora A1 - Isaacs, Aaron A1 - Abecasis, Goncalo R A1 - Schminke, Ulf A1 - Post, Wendy S A1 - Smith, Albert V A1 - Cupples, L Adrienne A1 - Markus, Hugh S A1 - Schmidt, Reinhold A1 - Huffman, Jennifer E A1 - Lehtimäki, Terho A1 - Baumert, Jens A1 - Münzel, Thomas A1 - Heckbert, Susan R A1 - Dehghan, Abbas A1 - North, Kari A1 - Oostra, Ben A1 - Bevan, Steve A1 - Stoegerer, Eva-Maria A1 - Hayward, Caroline A1 - Raitakari, Olli A1 - Meisinger, Christa A1 - Schillert, Arne A1 - Sanna, Serena A1 - Völzke, Henry A1 - Cheng, Yu-Ching A1 - Thorsson, Bolli A1 - Fox, Caroline S A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Nambi, Vijay A1 - Halperin, Eran A1 - Petrovic, Katja E A1 - Peltonen, Leena A1 - Wichmann, H Erich A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Parsa, Afshin A1 - Aspelund, Thor A1 - Demissie, Serkalem A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Taylor, Kent A1 - Uitterlinden, Andre A1 - Couper, David J A1 - Sitzer, Matthias A1 - Kähönen, Mika A1 - Illig, Thomas A1 - Wild, Philipp S A1 - Orrù, Marco A1 - Lüdemann, Jan A1 - Shuldiner, Alan R A1 - Eiriksdottir, Gudny A1 - White, Charles C A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Seissler, Jochen A1 - Zeller, Tanja A1 - Usala, Gianluca A1 - Ernst, Florian A1 - Launer, Lenore J A1 - D'Agostino, Ralph B A1 - O'Leary, Daniel H A1 - Ballantyne, Christie A1 - Thiery, Joachim A1 - Ziegler, Andreas A1 - Lakatta, Edward G A1 - Chilukoti, Ravi Kumar A1 - Harris, Tamara B A1 - Wolf, Philip A A1 - Psaty, Bruce M A1 - Polak, Joseph F A1 - Li, Xia A1 - Rathmann, Wolfgang A1 - Uda, Manuela A1 - Boerwinkle, Eric A1 - Klopp, Norman A1 - Schmidt, Helena A1 - Wilson, James F A1 - Viikari, Jorma A1 - Koenig, Wolfgang A1 - Blankenberg, Stefan A1 - Newman, Anne B A1 - Witteman, Jacqueline A1 - Heiss, Gerardo A1 - Duijn, Cornelia van A1 - Scuteri, Angelo A1 - Homuth, Georg A1 - Mitchell, Braxton D A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Aging KW - Atherosclerosis KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Middle Aged KW - Phenotype KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract ER - TY - JOUR T1 - A phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains. JF - PLoS Genet Y1 - 2011 A1 - Avery, Christy L A1 - He, Qianchuan A1 - North, Kari E A1 - Ambite, José L A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Hindorff, Lucia A A1 - Kooperberg, Charles A1 - Meigs, James B A1 - Pankow, James S A1 - Pendergrass, Sarah A A1 - Psaty, Bruce M A1 - Ritchie, Marylyn D A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Wilkens, Lynne R A1 - Heiss, Gerardo A1 - Lin, Dan Yu KW - African Americans KW - Apolipoprotein C-I KW - Blood Glucose KW - Dyslipidemias KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome, Human KW - Humans KW - Metabolic Syndrome KW - Obesity, Abdominal KW - Phenotype KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable KW - Ubiquitin-Protein Ligases KW - Vascular Diseases AB -

Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.

VL - 7 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22022282?dopt=Abstract ER - TY - JOUR T1 - Apolipoprotein E and kidney function in older adults. JF - Clin Nephrol Y1 - 2012 A1 - Seshasai, Rebecca Kurnik A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Siscovick, David A1 - Shlipak, Michael G A1 - Rifkin, Dena E A1 - Sarnak, Mark J KW - Aged KW - Aged, 80 and over KW - Alleles KW - Apolipoproteins E KW - Confidence Intervals KW - Creatinine KW - Cross-Sectional Studies KW - Cystatin C KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genotype KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Male KW - Odds Ratio KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

BACKGROUND: Previous studies suggest that the ε4 and ε2 alleles of apolipoprotein E (APOE) may be associated with decreased and increased risks of CKD, respectively, but there are limited data in older adults. We evaluated the associations of apolipoprotein E alleles with kidney function among older adults in the cardiovascular health study (CHS).

METHODS: Caucasian participants had APOE allelic analysis and serum creatinine and cystatin C measured at baseline (n = 3,844 for cross sectional analysis) and in follow up (n = 3,226 for longitudinal analysis). APOE variation was evaluated as an additive model with number of ε2, ε3 and ε4 alleles. GFR was estimated using the CKD epidemiology equation (eGFRcreat) and the cystatin C demographic equation (eGFRcys). The primary outcome was CKD defined by eGFR < 60 ml/min/1.73 m2. The secondary outcome was rapid progression defined by annual loss of eGFR > 3 ml/min/1.73 m2.

RESULTS: Mean eGFRcreat was 72 ml/min/1.73 m2 (25% CKD). Compared with the ε3 allele, the APOE ε4 allele was associated with reduced risk of CKD by eGFRcreat: unadjusted odds ratio (OR) and 95% confidence interval (CI) 0.79 (0.67 - 0.93) per allele, fully adjusted OR (95% CI) 0.80 (0.68 - 0.96) per allele. Results were consistent using eGFRcys. There was no association of the ε2 allele with CKD or between the apolipoprotein E gene with rapid progression.

CONCLUSIONS: The apolipoprotein ε4 allele was associated with lower odds of CKD in elderly Caucasian individuals. Future research should confirm these findings in other races and explore mechanisms to explain these results.

VL - 78 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22874105?dopt=Abstract ER - TY - JOUR T1 - Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. JF - Circulation Y1 - 2012 A1 - Ix, Joachim H A1 - Biggs, Mary L A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R A1 - Zieman, Susan J A1 - Siscovick, David S A1 - Mozzaffarian, Dariush A1 - Jensen, Majken K A1 - Nelson, Lauren A1 - Ruderman, Neil A1 - Djoussé, Luc KW - African Continental Ancestry Group KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - alpha-2-HS-Glycoprotein KW - Body Mass Index KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Life Style KW - Lipids KW - Male KW - Pilot Projects KW - Prevalence KW - Proportional Hazards Models KW - Residence Characteristics KW - Risk Factors KW - Sex Distribution AB -

BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD).

METHODS AND RESULTS: Among 3710 community-living individuals ≥ 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 ± 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01).

CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those ≥ 75 years of age.

VL - 125 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22511752?dopt=Abstract ER - TY - JOUR T1 - Association of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe). JF - PLoS One Y1 - 2012 A1 - Patel, Sanjay R A1 - Goodloe, Robert A1 - De, Gourab A1 - Kowgier, Matthew A1 - Weng, Jia A1 - Buxbaum, Sarah G A1 - Cade, Brian A1 - Fulop, Tibor A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Hillman, David A1 - Larkin, Emma K A1 - Lauderdale, Diane S A1 - Li, Li A1 - Mukherjee, Sutapa A1 - Palmer, Lyle A1 - Zee, Phyllis A1 - Zhu, Xiaofeng A1 - Redline, Susan KW - Adult KW - African Americans KW - Aged KW - Alleles KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Polysomnography KW - Sleep Apnea, Obstructive AB -

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10(-6). Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.

VL - 7 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23155414?dopt=Abstract ER - TY - JOUR T1 - Associations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Carty, Cara L A1 - Bůzková, Petra A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Cole, Shelley A1 - Heiss, Gerardo A1 - Hindorff, Lucia A A1 - Howard, Barbara V A1 - Mann, Sue A1 - Martin, Lisa W A1 - Zhang, Ying A1 - Matise, Tara C A1 - Prentice, Ross A1 - Reiner, Alexander P A1 - Kooperberg, Charles KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Female KW - Genetics, Population KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Triglycerides AB -

BACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.

VL - 5 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22403240?dopt=Abstract ER - TY - JOUR T1 - Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JF - JAMA Y1 - 2012 A1 - Matsushita, Kunihiro A1 - Mahmoodi, Bakhtawar K A1 - Woodward, Mark A1 - Emberson, Jonathan R A1 - Jafar, Tazeen H A1 - Jee, Sun Ha A1 - Polkinghorne, Kevan R A1 - Shankar, Anoop A1 - Smith, David H A1 - Tonelli, Marcello A1 - Warnock, David G A1 - Wen, Chi-Pang A1 - Coresh, Josef A1 - Gansevoort, Ron T A1 - Hemmelgarn, Brenda R A1 - Levey, Andrew S KW - African Continental Ancestry Group KW - Aged KW - Algorithms KW - Asian Continental Ancestry Group KW - Cardiovascular Diseases KW - Cohort Studies KW - Decision Support Techniques KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Models, Theoretical KW - Risk Assessment KW - Sex Factors AB -

CONTEXT: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.

OBJECTIVE: To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics.

DESIGN, SETTING, AND PARTICIPANTS: A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.

MAIN OUTCOME MEASURES: All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years).

RESULTS: Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts.

CONCLUSION: The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.

VL - 307 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22570462?dopt=Abstract ER - TY - JOUR T1 - Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study. JF - J Clin Endocrinol Metab Y1 - 2012 A1 - Kaplan, Robert C A1 - Bůzková, Petra A1 - Cappola, Anne R A1 - Strickler, Howard D A1 - McGinn, Aileen P A1 - Mercer, Laina D A1 - Arnold, Alice M A1 - Pollak, Michael N A1 - Newman, Anne B KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Longitudinal Studies KW - Male KW - Mortality KW - Predictive Value of Tests KW - Risk Factors AB -

BACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.

STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.

RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10% decreases over time in IGF-I levels (CM = 29.6%), individuals who had at least 10% increases over time in IGF-I levels (CM = 24.7%), and individuals who had IGF-I levels remaining within ±10% over time (CM = 23.5%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.

CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.

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

BACKGROUND: Risk scores for prediction of coronary heart disease (CHD) in older adults are needed.

OBJECTIVE: To develop a sex-specific CHD risk prediction model for older adults that accounts for competing risks for death.

DESIGN: 2 observational cohort studies, using data from 4946 participants in the Cardiovascular Health Study (CHS) and 4303 participants in the Rotterdam Study (RS).

SETTING: Community settings in the United States (CHS) and Rotterdam, the Netherlands (RS).

PARTICIPANTS: Persons aged 65 years or older who were free of cardiovascular disease.

MEASUREMENTS: A composite of nonfatal myocardial infarction and coronary death.

RESULTS: During a median follow-up of 16.5 and 14.9 years, 1166 CHS and 698 RS participants had CHD events, respectively. Deaths from noncoronary causes largely exceeded the number of CHD events, complicating accurate CHD risk predictions. The prediction model had moderate ability to discriminate between events and nonevents (c-statistic, 0.63 in both U.S. and European men and 0.67 and 0.68 in U.S. and European women). The model was well-calibrated; predicted risks were in good agreement with observed risks. Compared with the Framingham point scores, the prediction model classified elderly U.S. persons into higher risk categories but elderly European persons into lower risk categories. Differences in classification accuracy were not consistent and depended on cohort and sex. Adding newer cardiovascular risk markers to the model did not substantially improve performance.

LIMITATION: The model may be less applicable in nonwhite populations, and the comparison Framingham model was not designed for adults older than 79 years.

CONCLUSION: A CHD risk prediction model that accounts for deaths from noncoronary causes among older adults provided well-calibrated risk estimates but was not substantially more accurate than Framingham point scores. Moreover, adding newer risk markers did not improve accuracy. These findings emphasize the difficulties of predicting CHD risk in elderly persons and the need to improve these predictions.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; The Netherlands Organisation for Scientific Research; and the Netherlands Organisation for Health Research and Development.

VL - 157 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22986376?dopt=Abstract ER - TY - JOUR T1 - Evolution and functional impact of rare coding variation from deep sequencing of human exomes. JF - Science Y1 - 2012 A1 - Tennessen, Jacob A A1 - Bigham, Abigail W A1 - O'Connor, Timothy D A1 - Fu, Wenqing A1 - Kenny, Eimear E A1 - Gravel, Simon A1 - McGee, Sean A1 - Do, Ron A1 - Liu, Xiaoming A1 - Jun, Goo A1 - Kang, Hyun Min A1 - Jordan, Daniel A1 - Leal, Suzanne M A1 - Gabriel, Stacey A1 - Rieder, Mark J A1 - Abecasis, Goncalo A1 - Altshuler, David A1 - Nickerson, Deborah A A1 - Boerwinkle, Eric A1 - Sunyaev, Shamil A1 - Bustamante, Carlos D A1 - Bamshad, Michael J A1 - Akey, Joshua M KW - African Americans KW - Disease KW - European Continental Ancestry Group KW - Evolution, Molecular KW - Exome KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome, Human KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Population Growth KW - Selection, Genetic AB -

As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111× in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.

VL - 337 IS - 6090 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22604720?dopt=Abstract ER - TY - JOUR T1 - Fine-mapping and initial characterization of QT interval loci in African Americans. JF - PLoS Genet Y1 - 2012 A1 - Avery, Christy L A1 - Sethupathy, Praveen A1 - Buyske, Steven A1 - He, Qianchuan A1 - Lin, Dan-Yu A1 - Arking, Dan E A1 - Carty, Cara L A1 - Duggan, David A1 - Fesinmeyer, Megan D A1 - Hindorff, Lucia A A1 - Jeff, Janina M A1 - Klein, Liviu A1 - Patton, Kristen K A1 - Peters, Ulrike A1 - Shohet, Ralph V A1 - Sotoodehnia, Nona A1 - Young, Alicia M A1 - Kooperberg, Charles A1 - Haiman, Christopher A A1 - Mohlke, Karen L A1 - Whitsel, Eric A A1 - North, Kari E KW - African Americans KW - Aged KW - Computational Biology KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors KW - Tachycardia KW - United States AB -

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. JF - Atherosclerosis Y1 - 2012 A1 - Wassel, Christina L A1 - Lamina, Claudia A1 - Nambi, Vijay A1 - Coassin, Stefan A1 - Mukamal, Kenneth J A1 - Ganesh, Santhi K A1 - Jacobs, David R A1 - Franceschini, Nora A1 - Papanicolaou, George J A1 - Gibson, Quince A1 - Yanek, Lisa R A1 - van der Harst, Pim A1 - Ferguson, Jane F A1 - Crawford, Dana C A1 - Waite, Lindsay L A1 - Allison, Matthew A A1 - Criqui, Michael H A1 - McDermott, Mary M A1 - Mehra, Reena A1 - Cupples, L Adrienne A1 - Hwang, Shih-Jen A1 - Redline, Susan A1 - Kaplan, Robert C A1 - Heiss, Gerardo A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Taylor, Herman A A1 - Eraso, Luis H A1 - Haun, Margot A1 - Li, Mingyao A1 - Meisinger, Christa A1 - O'Connell, Jeffrey R A1 - Shuldiner, Alan R A1 - Tybjærg-Hansen, Anne A1 - Frikke-Schmidt, Ruth A1 - Kollerits, Barbara A1 - Rantner, Barbara A1 - Dieplinger, Benjamin A1 - Stadler, Marietta A1 - Mueller, Thomas A1 - Haltmayer, Meinhard A1 - Klein-Weigel, Peter A1 - Summerer, Monika A1 - Wichmann, H-Erich A1 - Asselbergs, Folkert W A1 - Navis, Gerjan A1 - Mateo Leach, Irene A1 - Brown-Gentry, Kristin A1 - Goodloe, Robert A1 - Assimes, Themistocles L A1 - Becker, Diane M A1 - Cooke, John P A1 - Absher, Devin M A1 - Olin, Jeffrey W A1 - Mitchell, Braxton D A1 - Reilly, Muredach P A1 - Mohler, Emile R A1 - North, Kari E A1 - Reiner, Alexander P A1 - Kronenberg, Florian A1 - Murabito, Joanne M KW - Adult KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Aryl Hydrocarbon Hydroxylases KW - Cytochrome P-450 CYP2B6 KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Oxidoreductases, N-Demethylating KW - Peripheral Arterial Disease KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.

METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.

RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.

CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

VL - 222 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22361517?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. JF - Nat Genet Y1 - 2012 A1 - Estrada, Karol A1 - Styrkarsdottir, Unnur A1 - Evangelou, Evangelos A1 - Hsu, Yi-Hsiang A1 - Duncan, Emma L A1 - Ntzani, Evangelia E A1 - Oei, Ling A1 - Albagha, Omar M E A1 - Amin, Najaf A1 - Kemp, John P A1 - Koller, Daniel L A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Minster, Ryan L A1 - Moayyeri, Alireza A1 - Vandenput, Liesbeth A1 - Willner, Dana A1 - Xiao, Su-Mei A1 - Yerges-Armstrong, Laura M A1 - Zheng, Hou-Feng A1 - Alonso, Nerea A1 - Eriksson, Joel A1 - Kammerer, Candace M A1 - Kaptoge, Stephen K A1 - Leo, Paul J A1 - Thorleifsson, Gudmar A1 - Wilson, Scott G A1 - Wilson, James F A1 - Aalto, Ville A1 - Alen, Markku A1 - Aragaki, Aaron K A1 - Aspelund, Thor A1 - Center, Jacqueline R A1 - Dailiana, Zoe A1 - Duggan, David J A1 - Garcia, Melissa A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Hallmans, Göran A1 - Hocking, Lynne J A1 - Husted, Lise Bjerre A1 - Jameson, Karen A A1 - Khusainova, Rita A1 - Kim, Ghi Su A1 - Kooperberg, Charles A1 - Koromila, Theodora A1 - Kruk, Marcin A1 - Laaksonen, Marika A1 - LaCroix, Andrea Z A1 - Lee, Seung Hun A1 - Leung, Ping C A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nguyen, Tuan V A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Rose, Lynda M A1 - Scollen, Serena A1 - Siggeirsdottir, Kristin A1 - Smith, Albert V A1 - Svensson, Olle A1 - Trompet, Stella A1 - Trummer, Olivia A1 - van Schoor, Natasja M A1 - Woo, Jean A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Buckley, Brendan M A1 - Cheng, Sulin A1 - Christiansen, Claus A1 - Cooper, Cyrus A1 - Dedoussis, George A1 - Ford, Ian A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Kähönen, Mika A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza A1 - Koh, Jung-Min A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Leslie, William D A1 - Lips, Paul A1 - Ljunggren, Osten A1 - Lorenc, Roman S A1 - Marc, Janja A1 - Mellström, Dan A1 - Obermayer-Pietsch, Barbara A1 - Olmos, José M A1 - Pettersson-Kymmer, Ulrika A1 - Reid, David M A1 - Riancho, José A A1 - Ridker, Paul M A1 - Rousseau, François A1 - Slagboom, P Eline A1 - Tang, Nelson L S A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Viikari, Jorma A1 - Zarrabeitia, María T A1 - Aulchenko, Yurii S A1 - Castano-Betancourt, Martha A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Ingvarsson, Thorvaldur A1 - Johannsdottir, Hrefna A1 - Kwan, Tony A1 - Li, Rui A1 - Luben, Robert A1 - Medina-Gómez, Carolina A1 - Palsson, Stefan Th A1 - Reppe, Sjur A1 - Rotter, Jerome I A1 - Sigurdsson, Gunnar A1 - van Meurs, Joyce B J A1 - Verlaan, Dominique A1 - Williams, Frances M K A1 - Wood, Andrew R A1 - Zhou, Yanhua A1 - Gautvik, Kaare M A1 - Pastinen, Tomi A1 - Raychaudhuri, Soumya A1 - Cauley, Jane A A1 - Chasman, Daniel I A1 - Clark, Graeme R A1 - Cummings, Steven R A1 - Danoy, Patrick A1 - Dennison, Elaine M A1 - Eastell, Richard A1 - Eisman, John A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Jackson, Rebecca D A1 - Jones, Graeme A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Lorentzon, Mattias A1 - McCloskey, Eugene A1 - Mitchell, Braxton D A1 - Nandakumar, Kannabiran A1 - Nicholson, Geoffrey C A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Pols, Huibert A P A1 - Prince, Richard L A1 - Raitakari, Olli A1 - Reid, Ian R A1 - Robbins, John A1 - Sambrook, Philip N A1 - Sham, Pak Chung A1 - Shuldiner, Alan R A1 - Tylavsky, Frances A A1 - van Duijn, Cornelia M A1 - Wareham, Nick J A1 - Cupples, L Adrienne A1 - Econs, Michael J A1 - Evans, David M A1 - Harris, Tamara B A1 - Kung, Annie Wai Chee A1 - Psaty, Bruce M A1 - Reeve, Jonathan A1 - Spector, Timothy D A1 - Streeten, Elizabeth A A1 - Zillikens, M Carola A1 - Thorsteinsdottir, Unnur A1 - Ohlsson, Claes A1 - Karasik, David A1 - Richards, J Brent A1 - Brown, Matthew A A1 - Stefansson, Kari A1 - Uitterlinden, André G A1 - Ralston, Stuart H A1 - Ioannidis, John P A A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando KW - Bone Density KW - Computational Biology KW - European Continental Ancestry Group KW - Extracellular Matrix Proteins KW - Female KW - Femur Neck KW - Fractures, Bone KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Glycoproteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-5 KW - Lumbar Vertebrae KW - Male KW - Mitochondrial Membrane Transport Proteins KW - Osteoporosis KW - Phosphoproteins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Spectrin AB -

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

VL - 44 IS - 5 ER - TY - JOUR T1 - Impact of ancestry and common genetic variants on QT interval in African Americans. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Smith, J Gustav A1 - Avery, Christy L A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Meng, Yan A A1 - Smith, Erin N A1 - Palmer, Cameron A1 - Tanaka, Toshiko A1 - Mehra, Reena A1 - Butler, Anne M A1 - Young, Taylor A1 - Buxbaum, Sarah G A1 - Kerr, Kathleen F A1 - Berenson, Gerald S A1 - Schnabel, Renate B A1 - Li, Guo A1 - Ellinor, Patrick T A1 - Magnani, Jared W A1 - Chen, Wei A1 - Bis, Joshua C A1 - Curb, J David A1 - Hsueh, Wen-Chi A1 - Rotter, Jerome I A1 - Liu, Yongmei A1 - Newman, Anne B A1 - Limacher, Marian C A1 - North, Kari E A1 - Reiner, Alexander P A1 - Quibrera, P Miguel A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Solomon, Allen J A1 - Srinivasan, Sathanur R A1 - Alonso, Alvaro A1 - Wallace, Robert A1 - Redline, Susan A1 - Zhang, Zhu-Ming A1 - Post, Wendy S A1 - Zonderman, Alan B A1 - Taylor, Herman A A1 - Murray, Sarah S A1 - Ferrucci, Luigi A1 - Arking, Dan E A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - Newton-Cheh, Christopher KW - Adult KW - African Americans KW - Aged KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genealogy and Heraldry KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract ER - TY - JOUR T1 - Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2012 A1 - Sanders, Jason L A1 - Fitzpatrick, Annette L A1 - Boudreau, Robert M A1 - Arnold, Alice M A1 - Aviv, Abraham A1 - Kimura, Masayuki A1 - Fried, Linda F A1 - Harris, Tamara B A1 - Newman, Anne B KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Carotid Intima-Media Thickness KW - Chronic Disease KW - Cystatin C KW - European Continental Ancestry Group KW - Female KW - Humans KW - Leukocytes KW - Lung KW - Male KW - Middle Aged KW - Telomere Homeostasis AB -

BACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).

METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4% male, 86.8% white, and 13.2% black).

RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = -132 [47] bp, p < .01), age (β [SE] = -107 [46], p = .02) or carotid thickness (β [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35%.

CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.

VL - 67 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21934123?dopt=Abstract ER - TY - JOUR T1 - Lifetime risks of cardiovascular disease. JF - N Engl J Med Y1 - 2012 A1 - Berry, Jarett D A1 - Dyer, Alan A1 - Cai, Xuan A1 - Garside, Daniel B A1 - Ning, Hongyan A1 - Thomas, Avis A1 - Greenland, Philip A1 - Van Horn, Linda A1 - Tracy, Russell P A1 - Lloyd-Jones, Donald M KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - Cohort Effect KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Risk KW - Risk Assessment KW - Risk Factors KW - United States AB -

BACKGROUND: The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.

METHODS: We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.

RESULTS: We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.

CONCLUSIONS: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.).

VL - 366 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22276822?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

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

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

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

BACKGROUND: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.

METHODOLOGY/PRINCIPAL FINDINGS: We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.

CONCLUSIONS/SIGNIFICANCE: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

VL - 7 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22629316?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Racial differences in risks for first cardiovascular events and noncardiovascular death: the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. JF - Circulation Y1 - 2012 A1 - Feinstein, Matthew A1 - Ning, Hongyan A1 - Kang, Joseph A1 - Bertoni, Alain A1 - Carnethon, Mercedes A1 - Lloyd-Jones, Donald M KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Continental Population Groups KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Residence Characteristics KW - Risk Factors AB -

BACKGROUND: No studies have compared first cardiovascular disease (CVD) events and non-CVD death between races in a competing risks framework, which examines risks for numerous events simultaneously.

METHODS AND RESULTS: We used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races in 3 multicenter, National Heart, Lung, and Blood Institute-sponsored cohorts. Of 14 569 Atherosclerosis Risk in Communities (ARIC) study participants aged 45 to 64 years with mean follow-up of 10.5 years, 11.6% had CVD and 5.0% had non-CVD death as first events; among 4237 Cardiovascular Health Study (CHS) study participants aged 65 to 84 years and followed for 8.5 years, these figures were 43.2% and 15.7%, respectively. Middle-aged blacks were significantly more likely than whites to experience any CVD as a first event; this disparity disappeared by older adulthood and after adjustment for CVD risk factors. The pattern of results was similar for Multi-Ethnic Study of Atherosclerosis (MESA) participants. Traditional Cox and competing risks models yielded different results for coronary heart disease risk. Black men appeared somewhat more likely than white men to experience coronary heart disease with use of a standard Cox model (hazard ratio 1.06; 95% CI 0.90, 1.26), whereas they appeared less likely than white men to have a first coronary heart disease event with use of a competing risks model (hazard ratio, 0.77; 95% CI, 0.60, 1.00).

CONCLUSIONS: CVD affects blacks at an earlier age than whites; this may be attributable in part to elevated CVD risk factor levels among blacks. Racial disparities in first CVD incidence disappear by older adulthood. Competing risks analyses may yield somewhat different results than traditional Cox models and provide a complementary approach to examining risks for first CVD events.

VL - 126 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22693351?dopt=Abstract ER - TY - JOUR T1 - Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study. JF - Mech Ageing Dev Y1 - 2012 A1 - Burnett-Hartman, Andrea N A1 - Fitzpatrick, Annette L A1 - Kronmal, Richard A A1 - Psaty, Bruce M A1 - Jenny, Nancy S A1 - Bis, Josh C A1 - Tracy, Russ P A1 - Kimura, Masayuki A1 - Aviv, Abraham KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Leukocytes KW - Male KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - Risk KW - RNA KW - Sex Factors KW - Telomerase KW - Telomere AB -

Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.

VL - 133 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22449406?dopt=Abstract ER - TY - JOUR T1 - Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts. JF - Biomarkers Y1 - 2013 A1 - Oelsner, E C A1 - Pottinger, T D A1 - Burkart, K M A1 - Allison, M A1 - Buxbaum, S G A1 - Hansel, N N A1 - Kumar, R A1 - Larkin, E K A1 - Lange, L A A1 - Loehr, L R A1 - London, S J A1 - O'Connor, G T A1 - Papanicolaou, G A1 - Petrini, M F A1 - Rabinowitz, D A1 - Raghavan, S A1 - Redline, S A1 - Thyagarajan, B A1 - Tracy, R P A1 - Wilk, J B A1 - White, W B A1 - Rich, S S A1 - Barr, R G KW - African Continental Ancestry Group KW - Biomarkers KW - Cohort Studies KW - E-Selectin KW - Endothelin-1 KW - Endothelium, Vascular KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Humans KW - Intercellular Adhesion Molecule-1 KW - Lung KW - Male KW - Middle Aged KW - P-Selectin KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests KW - Spirometry AB -

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown.

OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables.

METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets.

RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative.

CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

VL - 18 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23557128?dopt=Abstract ER - TY - JOUR T1 - Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. JF - Am J Epidemiol Y1 - 2013 A1 - Zhang, Lili A1 - Spencer, Kylee L A1 - Voruganti, V Saroja A1 - Jorgensen, Neal W A1 - Fornage, Myriam A1 - Best, Lyle G A1 - Brown-Gentry, Kristin D A1 - Cole, Shelley A A1 - Crawford, Dana C A1 - Deelman, Ewa A1 - Franceschini, Nora A1 - Gaffo, Angelo L A1 - Glenn, Kimberly R A1 - Heiss, Gerardo A1 - Jenny, Nancy S A1 - Köttgen, Anna A1 - Li, Qiong A1 - Liu, Kiang A1 - Matise, Tara C A1 - North, Kari E A1 - Umans, Jason G A1 - Kao, W H Linda KW - Adult KW - African Americans KW - Age Distribution KW - ATP-Binding Cassette Transporters KW - Comorbidity KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Genome-Wide Association Study KW - Gout KW - Hormone Replacement Therapy KW - Humans KW - Indians, North American KW - Male KW - Mexican Americans KW - Middle Aged KW - Neoplasm Proteins KW - Polymorphism, Genetic KW - Postmenopause KW - Sex Distribution KW - United States KW - Uric Acid AB -

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

VL - 177 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23552988?dopt=Abstract ER - TY - JOUR T1 - Association of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Yu, Bing A1 - Barbalic, Maja A1 - Brautbar, Ariel A1 - Nambi, Vijay A1 - Hoogeveen, Ron C A1 - Tang, Weihong A1 - Mosley, Thomas H A1 - Rotter, Jerome I A1 - deFilippi, Christopher R A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Rice, Ken A1 - Heckbert, Susan R A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric KW - African Continental Ancestry Group KW - Atherosclerosis KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nuclear Receptor Coactivator 2 KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Residence Characteristics KW - Risk Factors KW - Troponin T AB -

BACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.

METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).

CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23247143?dopt=Abstract ER - TY - JOUR T1 - Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults. JF - Lipids Y1 - 2013 A1 - Mukamal, Kenneth J A1 - Wilk, Jemma B A1 - Biggs, Mary L A1 - Jensen, Majken K A1 - Ix, Joachim H A1 - Kizer, Jorge R A1 - Tracy, Russell P A1 - Zieman, Susan J A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Djoussé, Luc KW - African Americans KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Fatty Acid-Binding Proteins KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Haplotypes KW - Humans KW - Insulin KW - Linkage Disequilibrium KW - Male KW - Polymorphism, Single Nucleotide AB -

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

VL - 48 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24043587?dopt=Abstract ER - TY - JOUR T1 - Common variants in Mendelian kidney disease genes and their association with renal function. JF - J Am Soc Nephrol Y1 - 2013 A1 - Parsa, Afshin A1 - Fuchsberger, Christian A1 - Köttgen, Anna A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - de Andrade, Mariza A1 - Chasman, Daniel I A1 - Teumer, Alexander A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Kim, Young J A1 - Taliun, Daniel A1 - Li, Man A1 - Feitosa, Mary A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Rao, Madhumathi A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Couraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Hofer, Edith A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Kao, W Linda A1 - Böger, Carsten A KW - Databases, Genetic KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Mendelian Randomization Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic AB -

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

VL - 24 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract ER - TY - JOUR T1 - Discovery and refinement of loci associated with lipid levels. JF - Nat Genet Y1 - 2013 A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Do, Ron A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Ingi Eyjolfsson, Gudmundur A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Kathiresan, Sekar A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R KW - African Continental Ancestry Group KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipids KW - Triglycerides AB -

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

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

BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.

METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.

RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).

CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.

CLINICAL TRIAL REGISTRATION: NCT00000611.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23311614?dopt=Abstract ER - TY - JOUR T1 - Exploring psychosocial pathways between neighbourhood characteristics and stroke in older adults: the cardiovascular health study. JF - Age Ageing Y1 - 2013 A1 - Yan, Tingjian A1 - Escarce, José J A1 - Liang, Li-Jung A1 - Longstreth, W T A1 - Merkin, Sharon Stein A1 - Ovbiagele, Bruce A1 - Vassar, Stefanie D A1 - Seeman, Teresa A1 - Sarkisian, Catherine A1 - Brown, Arleen F KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Brain Ischemia KW - Depression KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Linear Models KW - Logistic Models KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Residence Characteristics KW - Risk Assessment KW - Risk Factors KW - Social Support KW - Socioeconomic Factors KW - Stroke KW - Time Factors KW - United States KW - Vulnerable Populations AB -

OBJECTIVES: to investigate whether psychosocial pathways mediate the association between neighbourhood socioeconomic disadvantage and stroke.

METHODS: prospective cohort study with a follow-up of 11.5 years.

SETTING: the Cardiovascular Health Study, a longitudinal population-based cohort study of older adults ≥65 years.

MEASUREMENTS: the primary outcome was adjudicated incident ischaemic stroke. Neighbourhood socioeconomic status (NSES) was measured using a composite of six census-tract variables. Psychosocial factors were assessed with standard measures for depression, social support and social networks.

RESULTS: of the 3,834 white participants with no prior stroke, 548 had an incident ischaemic stroke over the 11.5-year follow-up. Among whites, the incident stroke hazard ratio (HR) associated with living in the lowest relative to highest NSES quartile was 1.32 (95% CI = 1.01-1.73), in models adjusted for individual SES. Additional adjustment for psychosocial factors had a minimal effect on hazard of incident stroke (HR = 1.31, CI = 1.00-1.71). Associations between NSES and stroke incidence were not found among African-Americans (n = 785) in either partially or fully adjusted models.

CONCLUSIONS: psychosocial factors played a minimal role in mediating the effect of NSES on stroke incidence among white older adults.

VL - 42 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23264005?dopt=Abstract ER - TY - JOUR T1 - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. JF - PLoS Biol Y1 - 2013 A1 - Carlson, Christopher S A1 - Matise, Tara C A1 - North, Kari E A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Buyske, Steven A1 - Schumacher, Fredrick R A1 - Peters, Ulrike A1 - Franceschini, Nora A1 - Ritchie, Marylyn D A1 - Duggan, David J A1 - Spencer, Kylee L A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Thomas, Fridtjof A1 - Young, Alicia A1 - Carty, Cara A1 - Heiss, Gerardo A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Kooperberg, Charles L KW - African Americans KW - Asian Americans KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Lipids KW - Metagenomics KW - Oceanic Ancestry Group KW - Polymorphism, Single Nucleotide AB -

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

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

Genetic association studies thus far have used detailed diagnoses of alcoholism to identify loci associated with risk. This proof-of-concept analysis examined whether population data of lifetime heaviest alcohol consumption may be used to identify genetic loci that modulate risk. We conducted a genetic association study in European Americans between variants in approximately 2100 genes and alcohol consumption as part of the Candidate gene Association Resource project. We defined cases as individuals with a history of drinking 5 or more drinks per day almost every day of the week and controls as current light drinkers (1-5 drinks per week). We cross-validated identified single nucleotide polymorphisms in a meta-analysis of 2 cohorts of unrelated individuals--Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)--and in a separate cohort of related individuals--Framingham Heart Study (FHS). The most significant variant in the meta-analysis of ARIC and CHS was rs6933598 in methylenetetrahydrofolate dehydrogenase (P = 7.46 × 10(-05)) with a P value in FHS of 0.042. The top variants in FHS were rs12249562 in cubulin (P = 3.03 × 10(-05)) and rs9839267 near cholecystokinin (P = 3.05 × 10(-05)) with a P value of 0.019 for rs9839267 in CHS. We have here shown feasibility in evaluating lifetime incidence of heavy alcohol drinking from population-based studies for the purpose of conducting genetic association analyses.

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

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

VL - 8 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - Meigs, James B A1 - North, Kari E A1 - Schumacher, Fredrick R A1 - Bůzková, Petra A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Goodloe, Robert A1 - Spencer, Kylee L A1 - Voruganti, Venkata Saroja A1 - Howard, Barbara V A1 - Jackson, Rebecca A1 - Kolonel, Laurence N A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Monroe, Kristine R A1 - Mukamal, Kenneth A1 - Dilks, Holli H A1 - Pendergrass, Sarah A A1 - Nato, Andrew A1 - Wan, Peggy A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Florez, Jose C A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Pankow, James S KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomics KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.

METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.

RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.

CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24063630?dopt=Abstract ER - TY - JOUR T1 - Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. JF - Hum Mol Genet Y1 - 2013 A1 - Reiner, Alexander P A1 - Hartiala, Jaana A1 - Zeller, Tanja A1 - Bis, Joshua C A1 - Dupuis, Josée A1 - Fornage, Myriam A1 - Baumert, Jens A1 - Kleber, Marcus E A1 - Wild, Philipp S A1 - Baldus, Stephan A1 - Bielinski, Suzette J A1 - Fontes, João D A1 - Illig, Thomas A1 - Keating, Brendan J A1 - Lange, Leslie A A1 - Ojeda, Francisco A1 - Müller-Nurasyid, Martina A1 - Munzel, Thomas F A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Tang, W H Wilson A1 - Thorand, Barbara A1 - Erdmann, Jeanette A1 - Jacobs, David R A1 - Wilson, James G A1 - Koenig, Wolfgang A1 - Tracy, Russell P A1 - Blankenberg, Stefan A1 - März, Winfried A1 - Gross, Myron D A1 - Benjamin, Emelia J A1 - Hazen, Stanley L A1 - Allayee, Hooman KW - Adult KW - African Americans KW - Aged KW - Case-Control Studies KW - Complement Factor H KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Gene Expression Regulation, Enzymologic KW - Genetic Association Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Peroxidase KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

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

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

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

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

VL - 9 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Fox, Ervin R A1 - Musani, Solomon K A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Yu, Bing A1 - Ogunyankin, Kofo O A1 - Smith, Nicholas L A1 - Kutlar, Abdullah A1 - Glazer, Nicole L A1 - Post, Wendy S A1 - Paltoo, Dina N A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Duarte, Christine W A1 - Kardia, Sharon L A1 - Meyers, Kristin J A1 - Sun, Yan V A1 - Arnett, Donna K A1 - Patki, Amit A A1 - Sha, Jin A1 - Cui, Xiangqui A1 - Samdarshi, Tandaw E A1 - Penman, Alan D A1 - Bibbins-Domingo, Kirsten A1 - Bůzková, Petra A1 - Benjamin, Emelia J A1 - Bluemke, David A A1 - Morrison, Alanna C A1 - Heiss, Gerardo A1 - Carr, J Jeffrey A1 - Tracy, Russell P A1 - Mosley, Thomas H A1 - Taylor, Herman A A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Cappola, Thomas P A1 - Vasan, Ramachandran S KW - African Americans KW - Aged KW - Cohort Studies KW - Diastole KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. JF - Nat Genet Y1 - 2013 A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Mägi, Reedik A1 - Ganna, Andrea A1 - Wheeler, Eleanor A1 - Feitosa, Mary F A1 - Justice, Anne E A1 - Monda, Keri L A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gentilini, Davide A1 - Jackson, Anne U A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Willer, Cristen J A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Hu, Yi-Juan A1 - Lee, Sang Hong A1 - Liang, Liming A1 - Lin, Dan-Yu A1 - Min, Josine L A1 - Neale, Benjamin M A1 - Thorleifsson, Gudmar A1 - Yang, Jian A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - den Heijer, Martin A1 - Eklund, Niina A1 - Fischer, Krista A1 - Goel, Anuj A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Jarick, Ivonne A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - König, Inke R A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lamina, Claudia A1 - Lecoeur, Cécile A1 - Li, Guo A1 - Mangino, Massimo A1 - McArdle, Wendy L A1 - Medina-Gómez, Carolina A1 - Müller-Nurasyid, Martina A1 - Ngwa, Julius S A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Pechlivanis, Sonali A1 - Perola, Markus A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Rose, Lynda M A1 - Shi, Jianxin A1 - Shungin, Dmitry A1 - Smith, Albert Vernon A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Trip, Mieke D A1 - Tyrer, Jonathan A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Waite, Lindsay L A1 - Zhao, Jing Hua A1 - Absher, Devin A1 - Asselbergs, Folkert W A1 - Atalay, Mustafa A1 - Attwood, Antony P A1 - Balmforth, Anthony J A1 - Basart, Hanneke A1 - Beilby, John A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Connell, John M A1 - Cookson, William O A1 - de Faire, Ulf A1 - de Vegt, Femmie A1 - Dei, Mariano A1 - Dimitriou, Maria A1 - Edkins, Sarah A1 - Estrada, Karol A1 - Evans, David M A1 - Farrall, Martin A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Franke, Lude A1 - Frau, Francesca A1 - Gejman, Pablo V A1 - Grallert, Harald A1 - Grönberg, Henrik A1 - Gudnason, Vilmundur A1 - Hall, Alistair S A1 - Hall, Per A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Heath, Andrew C A1 - Hebebrand, Johannes A1 - Homuth, Georg A1 - Hu, Frank B A1 - Hunt, Sarah E A1 - Hyppönen, Elina A1 - Iribarren, Carlos A1 - Jacobs, Kevin B A1 - Jansson, John-Olov A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Khaw, Kay-Tee A1 - Kivimaki, Mika A1 - Koenig, Wolfgang A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laitinen, Jaana H A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lind, Lars A1 - Lindström, Jaana A1 - Liu, Jianjun A1 - Liuzzi, Antonio A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Madden, Pamela A A1 - Magnusson, Patrik K A1 - Manunta, Paolo A1 - Marek, Diana A1 - März, Winfried A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Mooser, Vincent A1 - Mühleisen, Thomas W A1 - Munroe, Patricia B A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Navis, Gerjan A1 - Nicholson, George A1 - Nohr, Ellen A A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Palotie, Aarno A1 - Peden, John F A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Pütter, Carolin A1 - Radhakrishnan, Aparna A1 - Raitakari, Olli A1 - Rendon, Augusto A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Saaristo, Timo E A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Shin, So-Youn A1 - Signorini, Stefano A1 - Sinisalo, Juha A1 - Skrobek, Boris A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Stark, Klaus A1 - Stephens, Jonathan C A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Stumvoll, Michael A1 - Swift, Amy J A1 - Theodoraki, Eirini V A1 - Thorand, Barbara A1 - Trégouët, David-Alexandre A1 - Tremoli, Elena A1 - van der Klauw, Melanie M A1 - van Meurs, Joyce B J A1 - Vermeulen, Sita H A1 - Viikari, Jorma A1 - Virtamo, Jarmo A1 - Vitart, Veronique A1 - Waeber, Gérard A1 - Wang, Zhaoming A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Winkelmann, Bernhard R A1 - Witteman, Jacqueline C M A1 - Wolffenbuttel, Bruce H R A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Amouyel, Philippe A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Dedoussis, George V A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hingorani, Aroon A1 - Hinney, Anke A1 - Hofman, Albert A1 - Hovingh, Kees G A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Kuh, Diana A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Levinson, Douglas F A1 - Martin, Nicholas G A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nieminen, Markku S A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ouwehand, Willem H A1 - Palmer, Lyle J A1 - Penninx, Brenda A1 - Power, Chris A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Rauramaa, Rainer A1 - Ridker, Paul M A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Vollenweider, Peter A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunian, Talin A1 - Heid, Iris M A1 - Hunter, David A1 - Kaplan, Robert C A1 - Karpe, Fredrik A1 - Moffatt, Miriam F A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Pawitan, Yudi A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Steinthorsdottir, Valgerdur A1 - Strachan, David P A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Visscher, Peter M A1 - Di Blasio, Anna Maria A1 - Hirschhorn, Joel N A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Meyre, David A1 - Scherag, Andre A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Loos, Ruth J F A1 - Ingelsson, Erik KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Case-Control Studies KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Meta-Analysis as Topic KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Waist-Hip Ratio AB -

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

VL - 45 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. JF - Am J Clin Nutr Y1 - 2013 A1 - Tanaka, Toshiko A1 - Ngwa, Julius S A1 - van Rooij, Frank J A A1 - Zillikens, M Carola A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Luan, Jian'an A1 - Mikkilä, Vera A1 - Renstrom, Frida A1 - Sonestedt, Emily A1 - Zhao, Jing Hua A1 - Chu, Audrey Y A1 - Qi, Lu A1 - Chasman, Daniel I A1 - de Oliveira Otto, Marcia C A1 - Dhurandhar, Emily J A1 - Feitosa, Mary F A1 - Johansson, Ingegerd A1 - Khaw, Kay-Tee A1 - Lohman, Kurt K A1 - Manichaikul, Ani A1 - McKeown, Nicola M A1 - Mozaffarian, Dariush A1 - Singleton, Andrew A1 - Stirrups, Kathleen A1 - Viikari, Jorma A1 - Ye, Zheng A1 - Bandinelli, Stefania A1 - Barroso, Inês A1 - Deloukas, Panos A1 - Forouhi, Nita G A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - North, Kari E A1 - Dimitriou, Maria A1 - Hallmans, Göran A1 - Kähönen, Mika A1 - Langenberg, Claudia A1 - Ordovas, Jose M A1 - Uitterlinden, André G A1 - Hu, Frank B A1 - Kalafati, Ioanna-Panagiota A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Johnson, Andrew A1 - Emilsson, Valur A1 - Schrack, Jennifer A A1 - Semba, Richard D A1 - Siscovick, David S A1 - Arnett, Donna K A1 - Borecki, Ingrid B A1 - Franks, Paul W A1 - Kritchevsky, Stephen B A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Orho-Melander, Marju A1 - Rotter, Jerome I A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Ferrucci, Luigi A1 - Dedoussis, George A1 - Cupples, L Adrienne A1 - Nettleton, Jennifer A KW - Alleles KW - Atherosclerosis KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fibroblast Growth Factors KW - Follow-Up Studies KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Life Style KW - Obesity KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Quantitative Trait Loci KW - Surveys and Questionnaires AB -

BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.

RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).

CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23636237?dopt=Abstract ER - TY - JOUR T1 - Height and risk of incident intraparenchymal hemorrhage: Atherosclerosis Risk in Communities and Cardiovascular Health study cohorts. JF - J Stroke Cerebrovasc Dis Y1 - 2013 A1 - Smith, Lindsay G A1 - Yatsuya, Hiroshi A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Folsom, Aaron R KW - African Americans KW - Aged KW - Body Height KW - Cerebral Hemorrhage KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Time Factors KW - United States AB -

BACKGROUND: Height is inversely associated with incident coronary disease and total stroke, but few studies have examined the association between height and intraparenchymal hemorrhage (IPH). We hypothesized that height would be inversely associated with incident IPH in the combined cohorts of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study.

METHODS: Data on Caucasian and African American participants were used to estimate the association of height at baseline with incident IPH verified by clinician review of medical records and imaging reports. Sex-specific Cox proportional hazards regression models were used to calculate hazard ratios.

RESULTS: A total of 20,983 participants initially free of stroke (11,788 women and 9195 men) were followed for an average of 15.9 years (standard deviation [SD] 5.1 years). Incident IPH occurred in 115 women and 73 men. Sex, but not age, race, study, or blood pressure, modified the association (P = .03). After adjustment for risk factors (age, systolic blood pressure, triglycerides, low-density lipoprotein cholesterol, fibrinogen, and race), among women, height was significantly inversely associated with incident IPH (hazard ratio [HR] per SD [6.3 cm] was 0.81; 95% confidence interval [CI] 0.66-0.99; P = .04). The HR for tertile 3 vs 1 in women was 0.63 (95% CI 0.37-1.08). Among men, height was not linearly associated with incident IPH (HR per SD [6.7 cm] was 1.09; 95% CI 0.84-1.40; P = .52).

CONCLUSIONS: This large prospective study provides evidence that shorter height may be a risk factor for incident IPH in women.

VL - 22 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22177930?dopt=Abstract ER - TY - JOUR T1 - Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study. JF - Atherosclerosis Y1 - 2013 A1 - Tehrani, David M A1 - Gardin, Julius M A1 - Yanez, David A1 - Hirsch, Calvin H A1 - Lloyd-Jones, Donald M A1 - Stein, Phyllis K A1 - Wong, Nathan D KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Inflammation KW - Interleukin-6 KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.

OBJECTIVE: Investigate inflammatory markers' individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).

METHODS: In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA₂) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA₂ values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA₂ was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.

RESULTS: CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA₂ tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.

CONCLUSION: The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.

VL - 231 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24267235?dopt=Abstract ER - TY - JOUR T1 - The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study. JF - Diabetes Y1 - 2013 A1 - Graff, Mariaelisa A1 - Gordon-Larsen, Penny A1 - Lim, Unhee A1 - Fowke, Jay H A1 - Love, Shelly-Ann A1 - Fesinmeyer, Megan A1 - Wilkens, Lynne R A1 - Vertilus, Shawyntee A1 - Ritchie, Marilyn D A1 - Prentice, Ross L A1 - Pankow, Jim A1 - Monroe, Kristine A1 - Manson, JoAnn E A1 - Le Marchand, Loïc A1 - Kuller, Lewis H A1 - Kolonel, Laurence N A1 - Hong, Ching P A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Gross, Myron D A1 - Goodloe, Robert A1 - Franceschini, Nora A1 - Carlson, Christopher S A1 - Buyske, Steven A1 - Bůzková, Petra A1 - Hindorff, Lucia A A1 - Matise, Tara C A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - North, Kari E KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Health Surveys KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - United States KW - Young Adult AB -

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

VL - 62 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23300277?dopt=Abstract ER - TY - JOUR T1 - Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - Atherosclerosis Y1 - 2013 A1 - Zhang, Lili A1 - Bůzková, Petra A1 - Wassel, Christina L A1 - Roman, Mary J A1 - North, Kari E A1 - Crawford, Dana C A1 - Boston, Jonathan A1 - Brown-Gentry, Kristin D A1 - Cole, Shelley A A1 - Deelman, Ewa A1 - Goodloe, Robert A1 - Wilson, Sarah A1 - Heiss, Gerardo A1 - Jenny, Nancy S A1 - Jorgensen, Neal W A1 - Matise, Tara C A1 - McClellan, Bob E A1 - Nato, Alejandro Q A1 - Ritchie, Marylyn D A1 - Franceschini, Nora A1 - Kao, W H Linda KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Asymptomatic Diseases KW - Carotid Artery Diseases KW - Carotid Intima-Media Thickness KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Humans KW - Indians, North American KW - Linear Models KW - Logistic Models KW - Male KW - Mexican Americans KW - Middle Aged KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - United States AB -

BACKGROUND: A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.

METHODS: Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.

RESULTS: None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3809 AA, and 5353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10(-5)), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).

CONCLUSIONS: We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.

VL - 228 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23587283?dopt=Abstract ER - TY - JOUR T1 - Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project. JF - J Am Coll Cardiol Y1 - 2013 A1 - Huffman, Mark D A1 - Berry, Jarett D A1 - Ning, Hongyan A1 - Dyer, Alan R A1 - Garside, Daniel B A1 - Cai, Xuan A1 - Daviglus, Martha L A1 - Lloyd-Jones, Donald M KW - Adolescent KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Anthropometry KW - Body Mass Index KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Health Surveys KW - Heart Failure KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prognosis KW - Risk Assessment KW - Severity of Illness Index KW - Sex Factors KW - Survival Analysis KW - Time Factors KW - United States KW - Young Adult AB -

OBJECTIVES: This study sought to estimate lifetime risk for heart failure (HF) by sex and race.

BACKGROUND: Prior estimates of lifetime risk for developing HF range from 20% to 33% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made.

METHODS: Using public-release and internal datasets from National Heart, Lung, and Blood Institute-sponsored cohorts, we estimated lifetime risks for developing HF to age 95 years, with death free of HF as the competing event, among participants in the CHA (Chicago Heart Association Detection Project in Industry), ARIC (Atherosclerosis Risk in Communities), and CHS (Cardiovascular Health Study) cohorts.

RESULTS: There were 39,578 participants (33,652 [85%] white; 5,926 [15%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30% to 42% in white men, 20% to 29% in black men, 32% to 39% in white women, and 24% to 46% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher blood pressure and body mass index at all ages in both blacks and whites, and did not diminish substantially with advancing index age.

CONCLUSIONS: These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.

VL - 61 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23500287?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies. JF - Int J Obes (Lond) Y1 - 2013 A1 - Smith, C E A1 - Ngwa, J A1 - Tanaka, T A1 - Qi, Q A1 - Wojczynski, M K A1 - Lemaitre, R N A1 - Anderson, J S A1 - Manichaikul, A A1 - Mikkilä, V A1 - van Rooij, F J A A1 - Ye, Z A1 - Bandinelli, S A1 - Frazier-Wood, A C A1 - Houston, D K A1 - Hu, F A1 - Langenberg, C A1 - McKeown, N M A1 - Mozaffarian, D A1 - North, K E A1 - Viikari, J A1 - Zillikens, M C A1 - Djoussé, L A1 - Hofman, A A1 - Kähönen, M A1 - Kabagambe, E K A1 - Loos, R J F A1 - Saylor, G B A1 - Forouhi, N G A1 - Liu, Y A1 - Mukamal, K J A1 - Chen, Y-D I A1 - Tsai, M Y A1 - Uitterlinden, A G A1 - Raitakari, O A1 - van Duijn, C M A1 - Arnett, D K A1 - Borecki, I B A1 - Cupples, L A A1 - Ferrucci, L A1 - Kritchevsky, S B A1 - Lehtimäki, T A1 - Qi, Lu A1 - Rotter, J I A1 - Siscovick, D S A1 - Wareham, N J A1 - Witteman, J C M A1 - Ordovás, J M A1 - Nettleton, J A KW - Adipose Tissue KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Europe KW - European Continental Ancestry Group KW - Fatty Acids KW - Female KW - Gene Frequency KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Low Density Lipoprotein Receptor-Related Protein-1 KW - Male KW - Middle Aged KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prevalence KW - United States AB -

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids.

DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800).

RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed.

CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

VL - 37 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23357958?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. JF - Circulation Y1 - 2013 A1 - Sabater-Lleal, Maria A1 - Huang, Jie A1 - Chasman, Daniel A1 - Naitza, Silvia A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Teumer, Alexander A1 - Reiner, Alex P A1 - Folkersen, Lasse A1 - Basu, Saonli A1 - Rudnicka, Alicja R A1 - Trompet, Stella A1 - Mälarstig, Anders A1 - Baumert, Jens A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Hottenga, Jouke J A1 - Shin, So-Youn A1 - Lopez, Lorna M A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Oudot-Mellakh, Tiphaine A1 - Wilson, James F A1 - Navarro, Pau A1 - Huffman, Jennifer E A1 - Zemunik, Tatijana A1 - Redline, Susan A1 - Mehra, Reena A1 - Pulanic, Drazen A1 - Rudan, Igor A1 - Wright, Alan F A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Curb, J David A1 - Wallace, Robert A1 - Liu, Simin A1 - Eaton, Charles B A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Bandinelli, Stefania A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Fornage, Myriam A1 - Green, David A1 - Gross, Myron A1 - Davies, Gail A1 - Harris, Sarah E A1 - Liewald, David C A1 - Starr, John M A1 - Williams, Frances M K A1 - Grant, Peter J A1 - Spector, Timothy D A1 - Strawbridge, Rona J A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofman, Albert A1 - van Dongen, Jenny A1 - Willemsen, Gonneke A1 - Boomsma, Dorret I A1 - Yao, Jie A1 - Swords Jenny, Nancy A1 - Haritunians, Talin A1 - McKnight, Barbara A1 - Lumley, Thomas A1 - Taylor, Kent D A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Gieger, Christian A1 - Illig, Thomas A1 - Grotevendt, Anne A1 - Homuth, Georg A1 - Völzke, Henry A1 - Kocher, Thomas A1 - Goel, Anuj A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Clarke, Robert A1 - Steri, Maristella A1 - Tarasov, Kirill V A1 - Sanna, Serena A1 - Schlessinger, David A1 - Stott, David J A1 - Sattar, Naveed A1 - Buckley, Brendan M A1 - Rumley, Ann A1 - Lowe, Gordon D A1 - McArdle, Wendy L A1 - Chen, Ming-Huei A1 - Tofler, Geoffrey H A1 - Song, Jaejoon A1 - Boerwinkle, Eric A1 - Folsom, Aaron R A1 - Rose, Lynda M A1 - Franco-Cereceda, Anders A1 - Teichert, Martina A1 - Ikram, M Arfan A1 - Mosley, Thomas H A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M A1 - Sudlow, Cathie L M A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Kooner, Jaspal S A1 - Danesh, John A1 - Nelson, Christopher P A1 - Erdmann, Jeanette A1 - Reilly, Muredach P A1 - Kathiresan, Sekar A1 - Schunkert, Heribert A1 - Morange, Pierre-Emmanuel A1 - Ferrucci, Luigi A1 - Eriksson, Johan G A1 - Jacobs, David A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - de Geus, Eco J C A1 - Tracy, Russell P A1 - Hayward, Caroline A1 - Koenig, Wolfgang A1 - Cucca, Francesco A1 - Jukema, J Wouter A1 - Eriksson, Per A1 - Seshadri, Sudha A1 - Markus, Hugh S A1 - Watkins, Hugh A1 - Samani, Nilesh J A1 - Wallaschofski, Henri A1 - Smith, Nicholas L A1 - Tregouet, David A1 - Ridker, Paul M A1 - Tang, Weihong A1 - Strachan, David P A1 - Hamsten, Anders A1 - O'Donnell, Christopher J KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Venous Thromboembolism KW - Young Adult AB -

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

VL - 128 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract ER - TY - JOUR T1 - Obesity is associated with a lower resting oxygen saturation in the ambulatory elderly: results from the cardiovascular health study. JF - Respir Care Y1 - 2013 A1 - Kapur, Vishesh K A1 - Wilsdon, Anthony G A1 - Au, David A1 - Avdalovic, Mark A1 - Enright, Paul A1 - Fan, Vincent S A1 - Hansel, Nadia N A1 - Heckbert, Susan R A1 - Jiang, Rui A1 - Krishnan, Jerry A A1 - Mukamal, Kenneth A1 - Yende, Sachin A1 - Barr, R Graham KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Obesity KW - Oximetry KW - Oxygen KW - Smoking KW - Waist Circumference AB -

BACKGROUND: The contribution of obesity to hypoxemia has not been reported in a community-based study. Our hypothesis was that increasing obesity would be independently associated with lower SpO2 in an ambulatory elderly population.

METHODS: The Cardiovascular Health Study ascertained resting SpO2 in 2,252 subjects over age 64. We used multiple linear regression to estimate the association of body mass index (BMI) with SpO2 and to adjust for potentially confounding factors. Covariates including age, sex, race, smoking, airway obstruction (based on spirometry), self reported diagnosis of emphysema, asthma, heart failure, and left ventricular function (by echocardiography) were evaluated.

RESULTS: Among 2,252 subjects the mean and median SpO2 were 97.6% and 98.0% respectively; 5% of subjects had SpO2 values below 95%. BMI was negatively correlated with SpO2 (Spearman R = -0.27, P < .001). The mean difference in SpO2 between the lowest and highest BMI categories (< 25 kg/m(2) and ≥ 35 kg/m(2)) was 1.33% (95% CI 0.89-1.78%). In multivariable linear regression analysis, SpO2 was significantly inversely associated with BMI (1.4% per 10 units of BMI, 95% CI 1.2-1.6, for whites/others, and 0.87% per 10 units of BMI, 95% CI 0.47-1.27, for African Americans).

CONCLUSIONS: We found a narrow distribution of SpO2 values in a community-based sample of ambulatory elderly. Obesity was a strong independent contributor to a low SpO2, with effects comparable to or greater than other factors clinically associated with lower SpO2.

VL - 58 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23107018?dopt=Abstract ER - TY - JOUR T1 - Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - Ann Hum Genet Y1 - 2013 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Franceschini, Nora A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Bůzková, Petra A1 - Schumacher, Fredrick R A1 - Eaton, Charles B A1 - Goodloe, Robert J A1 - Duggan, David J A1 - Haessler, Jeff A1 - Cochran, Barbara A1 - Henderson, Brian E A1 - Cheng, Iona A1 - Johnson, Karen C A1 - Carlson, Chris S A1 - Love, Shelly-Ann A1 - Brown-Gentry, Kristin A1 - Nato, Alejandro Q A1 - Quibrera, Miguel A1 - Anderson, Garnet A1 - Shohet, Ralph V A1 - Ambite, Jose Luis A1 - Wilkens, Lynne R A1 - Marchand, Loic Le A1 - Haiman, Christopher A A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Fornage, Myriam A1 - Crawford, Dana C KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.

VL - 77 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23808484?dopt=Abstract ER - TY - JOUR T1 - Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. JF - J Am Heart Assoc Y1 - 2013 A1 - Alonso, Alvaro A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Stepas, Katherine A A1 - Pencina, Michael J A1 - Moser, Carlee B A1 - Sinner, Moritz F A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Ellinor, Patrick T A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Benjamin, Emelia J KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Iceland KW - Incidence KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Netherlands KW - Proportional Hazards Models KW - Risk Assessment KW - Smoking KW - United States AB -

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract ER - TY - JOUR T1 - Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. JF - Arterioscler Thromb Vasc Biol Y1 - 2013 A1 - Reiner, Alex P A1 - Lange, Ethan M A1 - Jenny, Nancy S A1 - Chaves, Paulo H M A1 - Ellis, Jaclyn A1 - Li, Jin A1 - Walston, Jeremy A1 - Lange, Leslie A A1 - Cushman, Mary A1 - Tracy, Russell P KW - African Americans KW - Age Factors KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Chromosomes, Human, Pair 5 KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Haplotypes KW - Hexosyltransferases KW - Humans KW - Incidence KW - Inflammation Mediators KW - Linear Models KW - Lipopolysaccharide Receptors KW - Logistic Models KW - Male KW - Membrane Proteins KW - Multivariate Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.

METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.

CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

VL - 33 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23162014?dopt=Abstract ER - TY - JOUR T1 - A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - PLoS Genet Y1 - 2013 A1 - Peters, Ulrike A1 - North, Kari E A1 - Sethupathy, Praveen A1 - Buyske, Steve A1 - Haessler, Jeff A1 - Jiao, Shuo A1 - Fesinmeyer, Megan D A1 - Jackson, Rebecca D A1 - Kuller, Lew H A1 - Rajkovic, Aleksandar A1 - Lim, Unhee A1 - Cheng, Iona A1 - Schumacher, Fred A1 - Wilkens, Lynne A1 - Li, Rongling A1 - Monda, Keri A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Cooper, Richard A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Gu, C Charles A1 - Houston, Denise A1 - Bůzková, Petra A1 - Ritchie, Marylyn A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Hindorff, Lucia A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Kooperberg, Charles KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alleles KW - Body Mass Index KW - Chromosome Mapping KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Obesity KW - Proteins AB -

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

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

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract ER - TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. JF - PLoS One Y1 - 2014 A1 - Bis, Joshua C A1 - DeStefano, Anita A1 - Liu, Xiaoming A1 - Brody, Jennifer A A1 - Choi, Seung Hoan A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Shahar, Eyal A1 - Butler, Kenneth R A1 - Gottesman, Rebecca F A1 - Muzny, Donna A1 - Kovar, Christie L A1 - Psaty, Bruce M A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Gupta, Mayetri A1 - Wolf, Philip A A1 - van Duijn, Cornelia A1 - Gibbs, Richard A A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - Boerwinkle, Eric A1 - Seshadri, Sudha A1 - Fornage, Myriam KW - Cell Adhesion Molecules, Neuronal KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genetic Heterogeneity KW - Humans KW - Introns KW - Ischemia KW - Male KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Sequence Analysis, DNA AB -

BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.

METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).

CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24959832?dopt=Abstract ER - TY - JOUR T1 - Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events. JF - Eur J Prev Cardiol Y1 - 2014 A1 - Fowkes, F G R A1 - Murray, G D A1 - Butcher, I A1 - Folsom, A R A1 - Hirsch, A T A1 - Couper, D J A1 - deBacker, G A1 - Kornitzer, M A1 - Newman, A B A1 - Sutton-Tyrrell, K C A1 - Cushman, M A1 - Lee, A J A1 - Price, J F A1 - D'Agostino, R B A1 - Murabito, J M A1 - Norman, Pe A1 - Masaki, K H A1 - Bouter, L M A1 - Heine, R J A1 - Stehouwer, C D A A1 - McDermott, M M A1 - Stoffers, H E J H A1 - Knottnerus, J A A1 - Ogren, M A1 - Hedblad, B A1 - Koenig, W A1 - Meisinger, C A1 - Cauley, J A A1 - Franco, Oh A1 - Hunink, M G M A1 - Hofman, A A1 - Witteman, J C A1 - Criqui, M H A1 - Langer, R D A1 - Hiatt, W R A1 - Hamman, R F KW - Adult KW - Aged KW - Aged, 80 and over KW - Ankle Brachial Index KW - Cardiovascular Diseases KW - Europe KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Models, Statistical KW - Predictive Value of Tests KW - Prognosis KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Time Factors KW - United States KW - Young Adult AB -

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.

DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.

METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.

RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women.

CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

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

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

VL - 14 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23459443?dopt=Abstract ER - TY - JOUR T1 - Extreme deep white matter hyperintensity volumes are associated with African American race. JF - Cerebrovasc Dis Y1 - 2014 A1 - Nyquist, Paul A A1 - Bilgel, Murat S A1 - Gottesman, Rebecca A1 - Yanek, Lisa R A1 - Moy, Taryn F A1 - Becker, Lewis C A1 - Cuzzocreo, Jennifer A1 - Prince, Jerry A1 - Yousem, David M A1 - Becker, Diane M A1 - Kral, Brian G A1 - Vaidya, Dhananjay KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Cerebrovascular Disorders KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Prevalence KW - Risk Factors KW - White Matter AB -

BACKGROUND: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors.

METHODS: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl.

RESULTS: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26).

CONCLUSIONS: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.

VL - 37 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24686322?dopt=Abstract ER - TY - JOUR T1 - FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. JF - Hum Mol Genet Y1 - 2014 A1 - Qi, Qibin A1 - Kilpeläinen, Tuomas O A1 - Downer, Mary K A1 - Tanaka, Toshiko A1 - Smith, Caren E A1 - Sluijs, Ivonne A1 - Sonestedt, Emily A1 - Chu, Audrey Y A1 - Renstrom, Frida A1 - Lin, Xiaochen A1 - Ängquist, Lars H A1 - Huang, Jinyan A1 - Liu, Zhonghua A1 - Li, Yanping A1 - Asif Ali, Muhammad A1 - Xu, Min A1 - Ahluwalia, Tarunveer Singh A1 - Boer, Jolanda M A A1 - Chen, Peng A1 - Daimon, Makoto A1 - Eriksson, Johan A1 - Perola, Markus A1 - Friedlander, Yechiel A1 - Gao, Yu-Tang A1 - Heppe, Denise H M A1 - Holloway, John W A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Kim, Yu-Mi A1 - Laaksonen, Maarit A A1 - Jääskeläinen, Tiina A1 - Lee, Nanette R A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Lu, Wei A1 - Luben, Robert N A1 - Manichaikul, Ani A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Monda, Keri L A1 - Ngwa, Julius S A1 - Perusse, Louis A1 - van Rooij, Frank J A A1 - Xiang, Yong-Bing A1 - Wen, Wanqing A1 - Wojczynski, Mary K A1 - Zhu, Jingwen A1 - Borecki, Ingrid B A1 - Bouchard, Claude A1 - Cai, Qiuyin A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Hansen, Torben A1 - Christiansen, Lene A1 - Hofman, Albert A1 - Johansson, Ingegerd A1 - Jørgensen, Torben A1 - Karasawa, Shigeru A1 - Khaw, Kay-Tee A1 - Kim, Mi-Kyung A1 - Kristiansson, Kati A1 - Li, Huaixing A1 - Lin, Xu A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Mikkilä, Vera A1 - Mozaffarian, Dariush A1 - North, Kari A1 - Pedersen, Oluf A1 - Raitakari, Olli A1 - Rissanen, Harri A1 - Tuomilehto, Jaakko A1 - van der Schouw, Yvonne T A1 - Uitterlinden, André G A1 - Zillikens, M Carola A1 - Franco, Oscar H A1 - Shyong Tai, E A1 - Ou Shu, Xiao A1 - Siscovick, David S A1 - Toft, Ulla A1 - Verschuren, W M Monique A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Zheng, Wei A1 - Ridker, Paul M A1 - Kang, Jae H A1 - Liang, Liming A1 - Jensen, Majken K A1 - Curhan, Gary C A1 - Pasquale, Louis R A1 - Hunter, David J A1 - Mohlke, Karen L A1 - Uusitupa, Matti A1 - Cupples, L Adrienne A1 - Rankinen, Tuomo A1 - Orho-Melander, Marju A1 - Wang, Tao A1 - Chasman, Daniel I A1 - Franks, Paul W A1 - Sørensen, Thorkild I A A1 - Hu, Frank B A1 - Loos, Ruth J F A1 - Nettleton, Jennifer A A1 - Qi, Lu KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins AB -

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25104851?dopt=Abstract ER - TY - JOUR T1 - Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. JF - Hum Mol Genet Y1 - 2014 A1 - Yoneyama, Sachiko A1 - Guo, Yiran A1 - Lanktree, Matthew B A1 - Barnes, Michael R A1 - Elbers, Clara C A1 - Karczewski, Konrad J A1 - Padmanabhan, Sandosh A1 - Bauer, Florianne A1 - Baumert, Jens A1 - Beitelshees, Amber A1 - Berenson, Gerald S A1 - Boer, Jolanda M A A1 - Burke, Gregory A1 - Cade, Brian A1 - Chen, Wei A1 - Cooper-Dehoff, Rhonda M A1 - Gaunt, Tom R A1 - Gieger, Christian A1 - Gong, Yan A1 - Gorski, Mathias A1 - Heard-Costa, Nancy A1 - Johnson, Toby A1 - Lamonte, Michael J A1 - McDonough, Caitrin A1 - Monda, Keri L A1 - Onland-Moret, N Charlotte A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Ordovas, Jose A1 - Peter, Inga A1 - Peters, Annette A1 - Shaffer, Jonathan A1 - Shen, Haiqinq A1 - Smith, Erin A1 - Speilotes, Liz A1 - Thomas, Fridtjof A1 - Thorand, Barbara A1 - Monique Verschuren, W M A1 - Anand, Sonia S A1 - Dominiczak, Anna A1 - Davidson, Karina W A1 - Hegele, Robert A A1 - Heid, Iris A1 - Hofker, Marten H A1 - Huggins, Gordon S A1 - Illig, Thomas A1 - Johnson, Julie A A1 - Kirkland, Susan A1 - König, Wolfgang A1 - Langaee, Taimour Y A1 - McCaffery, Jeanne A1 - Melander, Olle A1 - Mitchell, Braxton D A1 - Munroe, Patricia A1 - Murray, Sarah S A1 - Papanicolaou, George A1 - Redline, Susan A1 - Reilly, Muredach A1 - Samani, Nilesh J A1 - Schork, Nicholas J A1 - van der Schouw, Yvonne T A1 - Shimbo, Daichi A1 - Shuldiner, Alan R A1 - Tobin, Martin D A1 - Wijmenga, Cisca A1 - Yusuf, Salim A1 - Hakonarson, Hakon A1 - Lange, Leslie A A1 - Demerath, Ellen W A1 - Fox, Caroline S A1 - North, Kari E A1 - Reiner, Alex P A1 - Keating, Brendan A1 - Taylor, Kira C KW - Adiposity KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Waist Circumference KW - Waist-Hip Ratio KW - Young Adult AB -

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

VL - 23 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract ER - TY - JOUR T1 - Genetic variants related to height and risk of atrial fibrillation: the cardiovascular health study. JF - Am J Epidemiol Y1 - 2014 A1 - Rosenberg, Michael A A1 - Kaplan, Robert C A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Newton-Cheh, Christopher A1 - Mukamal, Kenneth J KW - African Americans KW - Aged KW - Atrial Fibrillation KW - Body Height KW - Endonucleases KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Longitudinal Studies KW - Male KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors AB -

Increased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥ 65 years) enrolled in 1989-1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10(-8)). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets.

VL - 180 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24944287?dopt=Abstract ER - TY - JOUR T1 - Incidence of and risk factors for sick sinus syndrome in the general population. JF - J Am Coll Cardiol Y1 - 2014 A1 - Jensen, Paul N A1 - Gronroos, Noelle N A1 - Chen, Lin Y A1 - Folsom, Aaron R A1 - deFilippi, Chris A1 - Heckbert, Susan R A1 - Alonso, Alvaro KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Population Surveillance KW - Prospective Studies KW - Risk Factors KW - Sick Sinus Syndrome AB -

BACKGROUND: Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.

OBJECTIVES: This study sought to describe the epidemiology of SSS.

METHODS: This analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥ 50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.

RESULTS: During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro-B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.

CONCLUSIONS: Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.

VL - 64 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25104519?dopt=Abstract ER - TY - JOUR T1 - The influence of sex on cardiovascular outcomes associated with diabetes among older black and white adults. JF - J Diabetes Complications Y1 - 2014 A1 - Vimalananda, Varsha G A1 - Biggs, Mary L A1 - Rosenzweig, James L A1 - Carnethon, Mercedes R A1 - Meigs, James B A1 - Thacker, Evan L A1 - Siscovick, David S A1 - Mukamal, Kenneth J KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Coronary Disease KW - Diabetes Complications KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Regression Analysis KW - Retrospective Studies KW - Risk Factors KW - Sex Factors KW - Survival Rate AB -

AIMS: It is unknown whether sex differences in the association of diabetes with cardiovascular outcomes vary by race. We examined sex differences in the associations of diabetes with incident congestive heart failure (CHF) and coronary heart disease (CHD) between older black and white adults.

METHODS: We analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort study of community-dwelling individuals aged ≥65 from four US counties. We included 4817 participants (476 black women, 279 black men, 2447 white women and 1625 white men). We estimated event rates and multivariate-adjusted hazard ratios for incident CHF, CHD, and all-cause mortality by Cox regression and competing risk analyses.

RESULTS: Over a median follow-up of 12.5years, diabetes was more strongly associated with CHF among black women (HR, 2.42 [95% CI, 1.70-3.40]) than black men (1.39 [0.83-2.34]); this finding did not reach statistical significance (P for interaction=0.08). Female sex conferred a higher risk for a composite outcome of CHF and CHD among black participants (2.44 [1.82-3.26]) vs. (1.44 [0.97-2.12]), P for interaction=0.03). There were no significant sex differences in the HRs associated with diabetes for CHF among whites, or for CHD or all-cause mortality among blacks or whites. The three-way interaction between sex, race, and diabetes on risk of cardiovascular outcomes was not significant (P=0.07).

CONCLUSIONS: Overall, sex did not modify the cardiovascular risk associated with diabetes among older black or white adults. However, our results suggest that a possible sex interaction among older blacks merits further study.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24461547?dopt=Abstract ER - TY - JOUR T1 - Leukocyte telomere length and age at menopause. JF - Epidemiology Y1 - 2014 A1 - Gray, Kristen E A1 - Schiff, Melissa A A1 - Fitzpatrick, Annette L A1 - Kimura, Masayuki A1 - Aviv, Abraham A1 - Starr, Jacqueline R KW - Adult KW - Age of Onset KW - Aged KW - Aging KW - Alcohol Drinking KW - Body Mass Index KW - Educational Status KW - European Continental Ancestry Group KW - Female KW - Humans KW - Leukocytes KW - Linear Models KW - Menopause KW - Middle Aged KW - Motor Activity KW - Smoking KW - Telomere AB -

BACKGROUND: Telomere length is a marker of cellular aging that varies with the individual, is inherited, and is highly correlated across somatic cell types within persons. Interindividual variability of telomere length may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age.

METHODS: We evaluated the relationship between leukocyte telomere length and age at natural menopause in 486 white women ≥65 years of age. We fit linear regression models adjusted for age, income, education, body mass index, physical activity, smoking, and alcohol intake. We repeated the analysis in women with surgical menopause. We also performed sensitivity analyses excluding women (1) with unilateral oophorectomy, (2) who were nulliparous, or (3) reporting menopausal age <40 years, among other exclusions.

RESULTS: For every 1-kb increase in leukocyte telomere length, average age at natural menopause increased by 10.2 months (95% confidence interval = 1.3 to 19.0). There was no association among 179 women reporting surgical menopause. In all but one sensitivity analysis, the association between leukocyte telomere length and age at menopause became stronger. However, when excluding women with menopausal age <40 years, the association decreased to 7.5 months (-0.4 to 15.5).

CONCLUSIONS: Women with the longest leukocyte telomere length underwent menopause 3 years later than those with the shortest leukocyte telomere length. If an artifact, an association would likely also have been observed in women with surgical menopause. If these results are replicated, leukocyte telomere length may prove to be a useful predictor of age at menopause.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24213145?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in APOC3, triglycerides, and coronary disease. JF - N Engl J Med Y1 - 2014 A1 - Crosby, Jacy A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Crosslin, David R A1 - Stitziel, Nathan O A1 - Lange, Leslie A A1 - Lu, Yingchang A1 - Tang, Zheng-Zheng A1 - Zhang, He A1 - Hindy, George A1 - Masca, Nicholas A1 - Stirrups, Kathleen A1 - Kanoni, Stavroula A1 - Do, Ron A1 - Jun, Goo A1 - Hu, Youna A1 - Kang, Hyun Min A1 - Xue, Chenyi A1 - Goel, Anuj A1 - Farrall, Martin A1 - Duga, Stefano A1 - Merlini, Pier Angelica A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Olivieri, Oliviero A1 - Martinelli, Nicola A1 - Yin, Wu A1 - Reilly, Dermot A1 - Speliotes, Elizabeth A1 - Fox, Caroline S A1 - Hveem, Kristian A1 - Holmen, Oddgeir L A1 - Nikpay, Majid A1 - Farlow, Deborah N A1 - Assimes, Themistocles L A1 - Franceschini, Nora A1 - Robinson, Jennifer A1 - North, Kari E A1 - Martin, Lisa W A1 - DePristo, Mark A1 - Gupta, Namrata A1 - Escher, Stefan A A1 - Jansson, Jan-Håkan A1 - Van Zuydam, Natalie A1 - Palmer, Colin N A A1 - Wareham, Nicholas A1 - Koch, Werner A1 - Meitinger, Thomas A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Erbel, Raimund A1 - König, Inke R A1 - Kruppa, Jochen A1 - Degenhardt, Franziska A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ballantyne, Christie M A1 - Abecasis, Goncalo A1 - Ordovas, Jose M A1 - Melander, Olle A1 - Watkins, Hugh A1 - Orho-Melander, Marju A1 - Ardissino, Diego A1 - Loos, Ruth J F A1 - McPherson, Ruth A1 - Willer, Cristen J A1 - Erdmann, Jeanette A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Deloukas, Panos A1 - Schunkert, Heribert A1 - Wilson, James G A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Lin, Dan-Yu A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Nickerson, Deborah A A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Reiner, Alex P A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar KW - African Continental Ancestry Group KW - Apolipoprotein C-III KW - Coronary Disease KW - European Continental Ancestry Group KW - Exome KW - Genotype KW - Heterozygote KW - Humans KW - Liver KW - Mutation KW - Risk Factors KW - Sequence Analysis, DNA KW - Triglycerides AB -

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

VL - 371 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of loci associated with age at natural menopause in African-American women. JF - Hum Mol Genet Y1 - 2014 A1 - Chen, Christina T L A1 - Liu, Ching-Ti A1 - Chen, Gary K A1 - Andrews, Jeanette S A1 - Arnold, Alice M A1 - Dreyfus, Jill A1 - Franceschini, Nora A1 - Garcia, Melissa E A1 - Kerr, Kathleen F A1 - Li, Guo A1 - Lohman, Kurt K A1 - Musani, Solomon K A1 - Nalls, Michael A A1 - Raffel, Leslie J A1 - Smith, Jennifer A1 - Ambrosone, Christine B A1 - Bandera, Elisa V A1 - Bernstein, Leslie A1 - Britton, Angela A1 - Brzyski, Robert G A1 - Cappola, Anne A1 - Carlson, Christopher S A1 - Couper, David A1 - Deming, Sandra L A1 - Goodarzi, Mark O A1 - Heiss, Gerardo A1 - John, Esther M A1 - Lu, Xiaoning A1 - Le Marchand, Loïc A1 - Marciante, Kristin A1 - McKnight, Barbara A1 - Millikan, Robert A1 - Nock, Nora L A1 - Olshan, Andrew F A1 - Press, Michael F A1 - Vaiyda, Dhananjay A1 - Woods, Nancy F A1 - Taylor, Herman A A1 - Zhao, Wei A1 - Zheng, Wei A1 - Evans, Michele K A1 - Harris, Tamara B A1 - Henderson, Brian E A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Yongmei A1 - Mosley, Thomas H A1 - Psaty, Bruce A1 - Wellons, Melissa A1 - Windham, Beverly G A1 - Zonderman, Alan B A1 - Cupples, L Adrienne A1 - Demerath, Ellen W A1 - Haiman, Christopher A1 - Murabito, Joanne M A1 - Rajkovic, Aleksandar KW - African Americans KW - Age Factors KW - Chromosomes, Human KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Menopause KW - United States AB -

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

VL - 23 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24493794?dopt=Abstract ER - TY - JOUR T1 - Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. JF - J Am Coll Cardiol Y1 - 2014 A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Trompet, Stella A1 - Li, Guo A1 - Krijthe, Bouwe P A1 - Chasman, Daniel I A1 - Barnard, John A1 - Kleber, Marcus E A1 - Dörr, Marcus A1 - Ozaki, Kouichi A1 - Smith, Albert V A1 - Müller-Nurasyid, Martina A1 - Walter, Stefan A1 - Agarwal, Sunil K A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Chen, Lin Y A1 - Everett, Brendan M A1 - Ford, Ian A1 - Franco, Oscar H A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Kääb, Stefan A1 - Mahida, Saagar A1 - Kathiresan, Sekar A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - McKnight, Barbara A1 - McManus, David D A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Silbernagel, Guenther A1 - Smith, Jonathan D A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Taylor, Kent D A1 - Tomaschitz, Andreas A1 - Tsunoda, Tatsuhiko A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Murabito, Joanne M A1 - Sinner, Moritz F A1 - Gudnason, Vilmundur A1 - Felix, Stephan B A1 - März, Winfried A1 - Chung, Mina A1 - Albert, Christine M A1 - Stricker, Bruno H A1 - Tanaka, Toshihiro A1 - Heckbert, Susan R A1 - Jukema, J Wouter A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Ellinor, Patrick T KW - Adult KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Atrial Fibrillation KW - Chromosome Mapping KW - Chromosomes, Human, Pair 4 KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Homeodomain Proteins KW - Humans KW - Japan KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factors AB -

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

VL - 63 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24486271?dopt=Abstract ER - TY - JOUR T1 - Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. JF - Stroke Y1 - 2014 A1 - Ibrahim-Verbaas, Carla A A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Choi, Seung Hoan A1 - Psaty, Bruce M A1 - Meigs, James B A1 - Rao, Madhu A1 - Nalls, Mike A1 - Fontes, João D A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Ehret, Georg B A1 - Fox, Caroline S A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Schmidt, Helena A1 - Lahti, Jari A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Folsom, Aaron R A1 - Boerwinkle, Eric A1 - Rosamond, Wayne D A1 - Shahar, Eyal A1 - Gottesman, Rebecca F A1 - Koudstaal, Peter J A1 - Amin, Najaf A1 - Wieberdink, Renske G A1 - Dehghan, Abbas A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - DeStefano, Anita L A1 - Debette, Stephanie A1 - Xue, Luting A1 - Beiser, Alexa A1 - Wolf, Philip A A1 - DeCarli, Charles A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Area Under Curve KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - ROC Curve KW - Sex Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract ER - TY - JOUR T1 - Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. JF - Hum Mol Genet Y1 - 2014 A1 - Gordon, Adam S A1 - Tabor, Holly K A1 - Johnson, Andrew D A1 - Snively, Beverly M A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Ioannidis, John P A A1 - Peters, Ulrike A1 - Robinson, Jennifer G A1 - Sucheston, Lara E A1 - Wang, Danxin A1 - Sotoodehnia, Nona A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Jackson, Rebecca D A1 - Herrington, David M A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rieder, Mark J A1 - Bamshad, Michael J A1 - Nickerson, Deborah A KW - Cytochrome P-450 Enzyme System KW - Databases, Genetic KW - European Continental Ancestry Group KW - Exome KW - Humans KW - Pharmaceutical Preparations KW - Pharmacogenetics KW - Polymorphism, Genetic AB -

The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

VL - 23 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24282029?dopt=Abstract ER - TY - JOUR T1 - Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. JF - Circulation Y1 - 2014 A1 - Zakai, Neil A A1 - McClure, Leslie A A1 - Judd, Suzanne E A1 - Safford, Monika M A1 - Folsom, Aaron R A1 - Lutsey, Pamela L A1 - Cushman, Mary KW - African Continental Ancestry Group KW - Aged KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Prevalence KW - Proportional Hazards Models KW - Prospective Studies KW - Residence Characteristics KW - Risk Factors KW - United States KW - Venous Thromboembolism AB -

BACKGROUND: Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites. However, prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope.

METHODS AND RESULTS: We ascertained VTE from 3 prospective studies: the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Reasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438 090 person-years, 916 incident VTE events (302 in blacks) occurred in 51 149 individuals (17 318 blacks) who were followed up. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in the CHS (hazard ratio, 1.81; 95% confidence interval, 1.20-2.73) but not ARIC (hazard ratio, 1.21; 95% confidence interval, 0.96-1.54). In REGARDS, there was a significant region-by-race interaction (P=0.01): Blacks in the Southeast had a significantly higher rate of VTE than blacks in the rest of the United States (hazard ratio, 1.63; 95% confidence interval, 1.08-2.48) that was not seen in whites (hazard ratio, 0.83; 95% confidence interval, 0.61-1.14).

CONCLUSIONS: The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies or different regional rates of VTE. Further studies of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.

VL - 129 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24508826?dopt=Abstract ER - TY - JOUR T1 - Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar. JF - Kidney Int Y1 - 2014 A1 - Wen, Chi Pang A1 - Matsushita, Kunihiro A1 - Coresh, Josef A1 - Iseki, Kunitoshi A1 - Islam, Muhammad A1 - Katz, Ronit A1 - McClellan, William A1 - Peralta, Carmen A A1 - Wang, Haiyan A1 - de Zeeuw, Dick A1 - Astor, Brad C A1 - Gansevoort, Ron T A1 - Levey, Andrew S A1 - Levin, Adeera KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Asian Continental Ancestry Group KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Odds Ratio KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

Some suggest race-specific cutpoints for kidney measures to define and stage chronic kidney disease (CKD), but evidence for race-specific clinical impact is limited. To address this issue, we compared hazard ratios of estimated glomerular filtration rates (eGFR) and albuminuria across races using meta-regression in 1.1 million adults (75% Asians, 21% Whites, and 4% Blacks) from 45 cohorts. Results came mainly from 25 general population cohorts comprising 0.9 million individuals. The associations of lower eGFR and higher albuminuria with mortality and end-stage renal disease (ESRD) were largely similar across races. For example, in Asians, Whites, and Blacks, the adjusted hazard ratios (95% confidence interval) for eGFR 45-59 versus 90-104 ml/min per 1.73 m(2) were 1.3 (1.2-1.3), 1.1 (1.0-1.2), and 1.3 (1.1-1.7) for all-cause mortality, 1.6 (1.5-1.7), 1.4 (1.2-1.7), and 1.4 (0.7-2.9) for cardiovascular mortality, and 27.6 (11.1-68.7), 11.2 (6.0-20.9), and 4.1 (2.2-7.5) for ESRD, respectively. The corresponding hazard ratios for urine albumin-to-creatinine ratio 30-299 mg/g or dipstick 1+ versus an albumin-to-creatinine ratio under 10 or dipstick negative were 1.6 (1.4-1.8), 1.7 (1.5-1.9), and 1.8 (1.7-2.1) for all-cause mortality, 1.7 (1.4-2.0), 1.8 (1.5-2.1), and 2.8 (2.2-3.6) for cardiovascular mortality, and 7.4 (2.0-27.6), 4.0 (2.8-5.9), and 5.6 (3.4-9.2) for ESRD, respectively. Thus, the relative mortality or ESRD risks of lower eGFR and higher albuminuria were largely similar among three major races, supporting similar clinical approach to CKD definition and staging, across races.

VL - 86 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24522492?dopt=Abstract ER - TY - JOUR T1 - Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Bis, Joshua C A1 - White, Charles C A1 - Franceschini, Nora A1 - Brody, Jennifer A1 - Zhang, Xiaoling A1 - Muzny, Donna A1 - Santibanez, Jireh A1 - Gibbs, Richard A1 - Liu, Xiaoming A1 - Lin, Honghuang A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - North, Kari E A1 - Cupples, L Adrienne A1 - O'Donnell, Christopher J KW - Aged KW - Aged, 80 and over KW - Aging KW - Atherosclerosis KW - Class Ib Phosphatidylinositol 3-Kinase KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA KW - Sodium-Phosphate Cotransporter Proteins, Type I AB -

BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).

METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).

CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951662?dopt=Abstract ER - TY - JOUR T1 - Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes. JF - Diabetologia Y1 - 2014 A1 - Tare, Archana A1 - Lane, Jacqueline M A1 - Cade, Brian E A1 - Grant, Struan F A A1 - Chen, Ting-Hsu A1 - Punjabi, Naresh M A1 - Lauderdale, Diane S A1 - Zee, Phyllis C A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Scheer, Frank A J L A1 - Redline, Susan A1 - Saxena, Richa KW - Blood Glucose KW - Body Composition KW - Body Mass Index KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Glucose Intolerance KW - Glycated Hemoglobin A KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sleep KW - Surveys and Questionnaires KW - Time Factors KW - United States AB -

AIMS/HYPOTHESIS: Short and long sleep duration are associated with increased risk of type 2 diabetes. We aimed to investigate whether genetic variants for fasting glucose or type 2 diabetes associate with short or long sleep duration and whether sleep duration modifies the association of genetic variants with these traits.

METHODS: We examined the cross-sectional relationship between self-reported habitual sleep duration and prevalence of type 2 diabetes in individuals of European descent participating in five studies included in the Candidate Gene Association Resource (CARe), totalling 1,474 cases and 8,323 controls. We tested for association of 16 fasting glucose-associated variants, 27 type 2 diabetes-associated variants and aggregate genetic risk scores with continuous and dichotomised (≤5 h or ≥9 h) sleep duration using regression models adjusted for age, sex and BMI. Finally, we tested whether a gene × behaviour interaction of variants with sleep duration had an impact on fasting glucose or type 2 diabetes risk.

RESULTS: Short sleep duration was significantly associated with type 2 diabetes in CARe (OR 1.32; 95% CI 1.08, 1.61; p = 0.008). Variants previously associated with fasting glucose or type 2 diabetes and genetic risk scores were not associated with sleep duration. Furthermore, no study-wide significant interaction was observed between sleep duration and these variants on glycaemic traits. Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1B rs4430796 in influencing risk of type 2 diabetes (p < 0.05).

CONCLUSIONS/INTERPRETATION: Our findings suggest that differences in habitual sleep duration do not mediate or modify the relationship between common variants underlying glycaemic traits (including in circadian rhythm genes) and diabetes.

VL - 57 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24280871?dopt=Abstract ER - TY - JOUR T1 - Systolic and diastolic blood pressure, incident cardiovascular events, and death in elderly persons: the role of functional limitation in the Cardiovascular Health Study. JF - Hypertension Y1 - 2014 A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Newman, Anne B A1 - Psaty, Bruce M A1 - Odden, Michelle C KW - Activities of Daily Living KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gait KW - Heart Rate KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Risk Factors KW - Survival Rate KW - Systole AB -

Whether limitation in the ability to perform activities of daily living (ADL) or gait speed can identify elders in whom the association of systolic and diastolic blood pressure (DBP) with cardiovascular events (CVDs) and death differs is unclear. We evaluated whether limitation in ADL or gait speed modifies the association of systolic blood pressure or DBP with incident CVD (n=2358) and death (n=3547) in the Cardiovascular Health Study. Mean age was 78±5 and 21% reported limitation in ≥1 ADL. There were 778 CVD and 1289 deaths over 9 years. Among persons without and those with ADL limitation, systolic blood pressure was associated with incident CVD: hazard ratio [HR] (per 10-mm Hg increase) 1.08 (95% confidence interval, 1.03, 1.13) and 1.06 (0.97, 1.17), respectively. ADL modified the association of DBP with incident CVD. Among those without ADL limitation, DBP was weakly associated with incident CVD, HR 1.04 (0.79, 1.37) for DBP >80, compared with <65 mm Hg. Among those with ADL limitation, DBP was inversely associated with CVD: HR 0.65 (0.44, 0.96) for DBP 66 to 80 mm Hg and HR 0.49 (0.25, 0.94) for DBP >80, compared with DBP ≤65. Among people with ADL limitation, a DBP of 66 to 80 had the lowest risk of death, HR 0.72 (0.57, 0.91), compared with a DBP of ≤65. Associations did not vary by 15-feet walking speed. ADL can identify elders in whom diastolic hypotension is associated with higher cardiovascular risk and death. Functional status, rather than chronologic age alone, should inform design of hypertension trials in elders.

VL - 64 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24935945?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic meta-analysis of white blood cell phenotypes. JF - Hum Mol Genet Y1 - 2014 A1 - Keller, Margaux F A1 - Reiner, Alexander P A1 - Okada, Yukinori A1 - van Rooij, Frank J A A1 - Johnson, Andrew D A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Morris, Andrew P A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Zonderman, Alan B A1 - Lettre, Guillaume A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Bandinelli, Stefania A1 - Qayyum, Rehan A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Kooperberg, Charles A1 - Keating, Brendan A1 - Reis, Jared A1 - Tang, Hua A1 - Boerwinkle, Eric A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Nakamura, Yusuke A1 - Kubo, Michiaki A1 - Liu, Simin A1 - Dehghan, Abbas A1 - Felix, Janine F A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Longo, Dan L A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Evans, Michelle K A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Takahashi, Atsushi A1 - Wilson, James G A1 - Ganesh, Santhi K A1 - Nalls, Mike A KW - African Americans KW - Asian Continental Ancestry Group KW - Bayes Theorem KW - European Continental Ancestry Group KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Linkage Disequilibrium KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract ER - TY - JOUR T1 - Association of exome sequences with plasma C-reactive protein levels in >9000 participants. JF - Hum Mol Genet Y1 - 2015 A1 - Schick, Ursula M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Lin, Honghuang A1 - Wei, Peng A1 - Pankratz, Nathan A1 - Lange, Leslie A A1 - Brody, Jennifer A1 - Stitziel, Nathan O A1 - Kim, Daniel S A1 - Carlson, Christopher S A1 - Fornage, Myriam A1 - Haessler, Jeffery A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Leal, Suzanne M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Tracy, Russell A1 - Ardissino, Diego A1 - Shah, Svati A1 - Willer, Cristen A1 - Loos, Ruth A1 - Melander, Olle A1 - McPherson, Ruth A1 - Hovingh, Kees A1 - Reilly, Muredach A1 - Watkins, Hugh A1 - Girelli, Domenico A1 - Fontanillas, Pierre A1 - Chasman, Daniel I A1 - Gabriel, Stacey B A1 - Gibbs, Richard A1 - Nickerson, Deborah A A1 - Kathiresan, Sekar A1 - Peters, Ulrike A1 - Dupuis, Josée A1 - Wilson, James G A1 - Rich, Stephen S A1 - Morrison, Alanna C A1 - Benjamin, Emelia J A1 - Gross, Myron D A1 - Reiner, Alex P KW - Adult KW - African Americans KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hepatocyte Nuclear Factor 1-alpha KW - Humans KW - Male KW - Plasma KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors AB -

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

VL - 24 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract ER - TY - JOUR T1 - Association of mitochondrial DNA levels with frailty and all-cause mortality. JF - J Mol Med (Berl) Y1 - 2015 A1 - Ashar, Foram N A1 - Moes, Anna A1 - Moore, Ann Z A1 - Grove, Megan L A1 - Chaves, Paulo H M A1 - Coresh, Josef A1 - Newman, Anne B A1 - Matteini, Amy M A1 - Bandeen-Roche, Karen A1 - Boerwinkle, Eric A1 - Walston, Jeremy D A1 - Arking, Dan E KW - African Americans KW - Aged KW - Aged, 80 and over KW - Aging KW - DNA, Mitochondrial KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Dosage KW - Geriatric Assessment KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Mortality KW - Odds Ratio KW - Population Surveillance KW - Prospective Studies KW - Surveys and Questionnaires KW - United States AB -

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3% men) from CHS and 11,509 participants (44.9% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

VL - 93 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25471480?dopt=Abstract ER - TY - JOUR T1 - Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Yu, Bing A1 - Li, Alexander H A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - de Vries, Paul S A1 - Bis, Joshua C A1 - Musani, Solomon K A1 - Alexander, Danny A1 - Morrison, Alanna C A1 - Franco, Oscar H A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Dehghan, Abbas A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Gibbs, Richard A1 - Wei, Peng A1 - Boerwinkle, Eric KW - Adult KW - African Americans KW - Alleles KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Histidine KW - Histidine Ammonia-Lyase KW - Humans KW - Male KW - Mutation AB -

BACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.

METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.

CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25575548?dopt=Abstract ER - TY - JOUR T1 - Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study. JF - J Thromb Haemost Y1 - 2015 A1 - Olson, N C A1 - Butenas, S A1 - Lange, L A A1 - Lange, E M A1 - Cushman, M A1 - Jenny, N S A1 - Walston, J A1 - Souto, J C A1 - Soria, J M A1 - Chauhan, G A1 - Debette, S A1 - Longstreth, W T A1 - Seshadri, S A1 - Reiner, A P A1 - Tracy, R P KW - African Americans KW - Age Factors KW - Aged KW - Blood Coagulation KW - Brain Ischemia KW - European Continental Ancestry Group KW - Factor XII KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Humans KW - Incidence KW - Male KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Stroke KW - Thrombin KW - Time Factors KW - United States AB -

BACKGROUND: The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts.

OBJECTIVES: To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke.

PATIENTS/METHODS: We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n = 5411), both with and without inhibitory anti-factor XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~ 50 000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2 years.

RESULTS: The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β = - 34.2 ± 3.5 nm; P = 3.3 × 10(-22) ; minor allele frequency [MAF] = 0.23) and African-Americans (β = - 31.1 ± 7.9 nm; P = 9.0 × 10(-5) ; MAF = 0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (β = 16.3 nm; P = 4.3 × 10(-9) ; MAF = 0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01-1.17; P = 0.03) for pTG, 1.06 (95% CI 0.98-1.15; P = 0.17) for pTG/FXIa(-) , and 1.11 (95% CI 1.02-1.21; P = 0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n = 834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β = - 0.02; standard error = 0.08; P = 0.81).

CONCLUSIONS: These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex vivo and in vivo.

VL - 13 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26286125?dopt=Abstract ER - TY - JOUR T1 - Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. JF - PLoS One Y1 - 2015 A1 - Bis, Joshua C A1 - Sitlani, Colleen A1 - Irvin, Ryan A1 - Avery, Christy L A1 - Smith, Albert Vernon A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Musani, Solomon K A1 - Li, Xiaohui A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Harris, Tamara B A1 - Quibrera, P Miguel A1 - Brody, Jennifer A A1 - Demissie, Serkalem A1 - Davis, Barry R A1 - Wiggins, Kerri L A1 - Tranah, Gregory J A1 - Lange, Leslie A A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Franco, Oscar H A1 - Launer, Lenore J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Cupples, L Adrienne A1 - Eckfeldt, John H A1 - Smith, Nicholas L A1 - Liu, Yongmei A1 - Wilson, James G A1 - Heckbert, Susan R A1 - Buckley, Brendan M A1 - Ikram, M Arfan A1 - Boerwinkle, Eric A1 - Chen, Yii-Der Ida A1 - de Craen, Anton J M A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Ford, Ian A1 - Hofman, Albert A1 - Sattar, Naveed A1 - Slagboom, P Eline A1 - Westendorp, Rudi G J A1 - Gudnason, Vilmundur A1 - Vasan, Ramachandran S A1 - Lumley, Thomas A1 - Cummings, Steven R A1 - Taylor, Herman A A1 - Post, Wendy A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Whitsel, Eric A A1 - Psaty, Bruce M A1 - Arnett, Donna KW - African Americans KW - Aged KW - Antihypertensive Agents KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Treatment Outcome AB -

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract ER - TY - JOUR T1 - Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. JF - Hum Mol Genet Y1 - 2015 A1 - Nettleton, Jennifer A A1 - Follis, Jack L A1 - Ngwa, Julius S A1 - Smith, Caren E A1 - Ahmad, Shafqat A1 - Tanaka, Toshiko A1 - Wojczynski, Mary K A1 - Voortman, Trudy A1 - Lemaitre, Rozenn N A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Houston, Denise K A1 - Perälä, Mia-Maria A1 - Qi, Qibin A1 - Sonestedt, Emily A1 - Manichaikul, Ani A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Mikkilä, Vera A1 - North, Kari E A1 - Siscovick, David S A1 - Harald, Kennet A1 - McKeown, Nicola M A1 - Johansson, Ingegerd A1 - Rissanen, Harri A1 - Liu, Yongmei A1 - Lahti, Jari A1 - Hu, Frank B A1 - Bandinelli, Stefania A1 - Rukh, Gull A1 - Rich, Stephen A1 - Booij, Lisanne A1 - Dmitriou, Maria A1 - Ax, Erika A1 - Raitakari, Olli A1 - Mukamal, Kenneth A1 - Männistö, Satu A1 - Hallmans, Göran A1 - Jula, Antti A1 - Ericson, Ulrika A1 - Jacobs, David R A1 - van Rooij, Frank J A A1 - Deloukas, Panos A1 - Sjogren, Per A1 - Kähönen, Mika A1 - Djoussé, Luc A1 - Perola, Markus A1 - Barroso, Inês A1 - Hofman, Albert A1 - Stirrups, Kathleen A1 - Viikari, Jorma A1 - Uitterlinden, André G A1 - Kalafati, Ioanna P A1 - Franco, Oscar H A1 - Mozaffarian, Dariush A1 - Salomaa, Veikko A1 - Borecki, Ingrid B A1 - Knekt, Paul A1 - Kritchevsky, Stephen B A1 - Eriksson, Johan G A1 - Dedoussis, George V A1 - Qi, Lu A1 - Ferrucci, Luigi A1 - Orho-Melander, Marju A1 - Zillikens, M Carola A1 - Ingelsson, Erik A1 - Lehtimäki, Terho A1 - Renstrom, Frida A1 - Cupples, L Adrienne A1 - Loos, Ruth J F A1 - Franks, Paul W KW - Adult KW - Body Mass Index KW - Case-Control Studies KW - Diet, Western KW - Epistasis, Genetic KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

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

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.

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

OBJECTIVE: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.

RESEARCH DESIGN AND METHODS: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

RESULTS: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).

CONCLUSIONS: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

VL - 38 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract ER - TY - JOUR T1 - Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. JF - Am J Clin Nutr Y1 - 2015 A1 - Mozaffarian, Dariush A1 - Kabagambe, Edmond K A1 - Johnson, Catherine O A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - Sun, Qi A1 - Foy, Millennia A1 - Wang, Lu A1 - Wiener, Howard A1 - Irvin, Marguerite R A1 - Rich, Stephen S A1 - Wu, Hongyu A1 - Jensen, Majken K A1 - Chasman, Daniel I A1 - Chu, Audrey Y A1 - Fornage, Myriam A1 - Steffen, Lyn A1 - King, Irena B A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Djoussé, Luc A1 - Chen, Ida Y-D A1 - Wu, Jason H Y A1 - Siscovick, David S A1 - Ridker, Paul M A1 - Tsai, Michael Y A1 - Rimm, Eric B A1 - Hu, Frank B A1 - Arnett, Donna K KW - African Americans KW - Arachidonic Acid KW - Asian Americans KW - Biomarkers KW - European Continental Ancestry Group KW - Fatty Acids, Omega-6 KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Loci KW - Genotyping Techniques KW - Humans KW - Phospholipids KW - Polymorphism, Single Nucleotide KW - Trans Fatty Acids AB -

BACKGROUND: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.

OBJECTIVE: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.

DESIGN: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.

RESULTS: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 × 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 × 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans.

CONCLUSIONS: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.

VL - 101 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25646338?dopt=Abstract ER - TY - JOUR T1 - Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. JF - Am J Clin Nutr Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Lamon-Fava, Stefania A1 - Richardson, Kris A1 - Saxena, Richa A1 - Scheer, Frank A J L A1 - Kovanen, Leena A1 - Bartz, Traci M A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Frazier-Wood, Alexis C A1 - Kalafati, Ioanna-Panagiota A1 - Mikkilä, Vera A1 - Partonen, Timo A1 - Lemaitre, Rozenn N A1 - Lahti, Jari A1 - Hernandez, Dena G A1 - Toft, Ulla A1 - Johnson, W Craig A1 - Kanoni, Stavroula A1 - Raitakari, Olli T A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Grarup, Niels A1 - Highland, Heather M A1 - Rallidis, Loukianos A1 - Kähönen, Mika A1 - Havulinna, Aki S A1 - Siscovick, David S A1 - Räikkönen, Katri A1 - Jørgensen, Torben A1 - Rotter, Jerome I A1 - Deloukas, Panos A1 - Viikari, Jorma S A A1 - Mozaffarian, Dariush A1 - Linneberg, Allan A1 - Seppälä, Ilkka A1 - Hansen, Torben A1 - Salomaa, Veikko A1 - Gharib, Sina A A1 - Eriksson, Johan G A1 - Bandinelli, Stefania A1 - Pedersen, Oluf A1 - Rich, Stephen S A1 - Dedoussis, George A1 - Lehtimäki, Terho A1 - Ordovas, Jose M KW - Adult KW - Body Mass Index KW - CLOCK Proteins KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fatty Acids, Unsaturated KW - Female KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Sleep KW - Young Adult AB -

BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.

OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.

DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

RESULTS: We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.

CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.

VL - 101 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25527757?dopt=Abstract ER - TY - JOUR T1 - Integrative pathway genomics of lung function and airflow obstruction. JF - Hum Mol Genet Y1 - 2015 A1 - Gharib, Sina A A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Birkland, Timothy P A1 - Wilk, Jemma B A1 - Wain, Louise V A1 - Brody, Jennifer A A1 - Obeidat, Ma'en A1 - Hancock, Dana B A1 - Tang, Wenbo A1 - Rawal, Rajesh A1 - Boezen, H Marike A1 - Imboden, Medea A1 - Huffman, Jennifer E A1 - Lahousse, Lies A1 - Alves, Alexessander C A1 - Manichaikul, Ani A1 - Hui, Jennie A1 - Morrison, Alanna C A1 - Ramasamy, Adaikalavan A1 - Smith, Albert Vernon A1 - Gudnason, Vilmundur A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Evans, David M A1 - Strachan, David P A1 - Deary, Ian J A1 - Hofman, Albert A1 - Gläser, Sven A1 - Wilson, James F A1 - North, Kari E A1 - Zhao, Jing Hua A1 - Heckbert, Susan R A1 - Jarvis, Deborah L A1 - Probst-Hensch, Nicole A1 - Schulz, Holger A1 - Barr, R Graham A1 - Jarvelin, Marjo-Riitta A1 - O'Connor, George T A1 - Kähönen, Mika A1 - Cassano, Patricia A A1 - Hysi, Pirro G A1 - Dupuis, Josée A1 - Hayward, Caroline A1 - Psaty, Bruce M A1 - Hall, Ian P A1 - Parks, William C A1 - Tobin, Martin D A1 - London, Stephanie J KW - Airway Obstruction KW - Animals KW - Cell Proliferation KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Immune System KW - Lung KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Signal Transduction AB -

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

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

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract ER - TY - JOUR T1 - A Meta-analysis of the Association of Estimated GFR, Albuminuria, Age, Race, and Sex With Acute Kidney Injury. JF - Am J Kidney Dis Y1 - 2015 A1 - Grams, Morgan E A1 - Sang, Yingying A1 - Ballew, Shoshana H A1 - Gansevoort, Ron T A1 - Kimm, Heejin A1 - Kovesdy, Csaba P A1 - Naimark, David A1 - Oien, Cecilia A1 - Smith, David H A1 - Coresh, Josef A1 - Sarnak, Mark J A1 - Stengel, Bénédicte A1 - Tonelli, Marcello KW - Acute Kidney Injury KW - Adolescent KW - Adult KW - African Americans KW - Age Distribution KW - Aged KW - Albuminuria KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prognosis KW - Severity of Illness Index KW - Sex Distribution KW - Young Adult AB -

BACKGROUND: Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white).

STUDY DESIGN: Collaborative meta-analysis.

SETTING & POPULATION: 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants).

SELECTION CRITERIA FOR STUDIES: Available eGFR, ACR, and 50 or more AKI events.

PREDICTORS: Age, sex, race, eGFR, urine ACR, and interactions.

OUTCOME: Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.

RESULTS: 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80mL/min/1.73m(2), the adjusted HR of AKI at eGFR of 45mL/min/1.73m(2) was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5mg/g, the risk of AKI at ACR of 300mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR.

LIMITATIONS: Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code.

CONCLUSIONS: Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.

VL - 66 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25943717?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. JF - Mol Psychiatry Y1 - 2015 A1 - Gottlieb, D J A1 - Hek, K A1 - Chen, T-H A1 - Watson, N F A1 - Eiriksdottir, G A1 - Byrne, E M A1 - Cornelis, M A1 - Warby, S C A1 - Bandinelli, S A1 - Cherkas, L A1 - Evans, D S A1 - Grabe, H J A1 - Lahti, J A1 - Li, M A1 - Lehtimäki, T A1 - Lumley, T A1 - Marciante, K D A1 - Pérusse, L A1 - Psaty, B M A1 - Robbins, J A1 - Tranah, G J A1 - Vink, J M A1 - Wilk, J B A1 - Stafford, J M A1 - Bellis, C A1 - Biffar, R A1 - Bouchard, C A1 - Cade, B A1 - Curhan, G C A1 - Eriksson, J G A1 - Ewert, R A1 - Ferrucci, L A1 - Fülöp, T A1 - Gehrman, P R A1 - Goodloe, R A1 - Harris, T B A1 - Heath, A C A1 - Hernandez, D A1 - Hofman, A A1 - Hottenga, J-J A1 - Hunter, D J A1 - Jensen, M K A1 - Johnson, A D A1 - Kähönen, M A1 - Kao, L A1 - Kraft, P A1 - Larkin, E K A1 - Lauderdale, D S A1 - Luik, A I A1 - Medici, M A1 - Montgomery, G W A1 - Palotie, A A1 - Patel, S R A1 - Pistis, G A1 - Porcu, E A1 - Quaye, L A1 - Raitakari, O A1 - Redline, S A1 - Rimm, E B A1 - Rotter, J I A1 - Smith, A V A1 - Spector, T D A1 - Teumer, A A1 - Uitterlinden, A G A1 - Vohl, M-C A1 - Widen, E A1 - Willemsen, G A1 - Young, T A1 - Zhang, X A1 - Liu, Y A1 - Blangero, J A1 - Boomsma, D I A1 - Gudnason, V A1 - Hu, F A1 - Mangino, M A1 - Martin, N G A1 - O'Connor, G T A1 - Stone, K L A1 - Tanaka, T A1 - Viikari, J A1 - Gharib, S A A1 - Punjabi, N M A1 - Räikkönen, K A1 - Völzke, H A1 - Mignot, E A1 - Tiemeier, H KW - Adult KW - African Americans KW - Aged KW - Dyssomnias KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Self Report KW - Sleep AB -

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

VL - 20 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25469926?dopt=Abstract ER - TY - JOUR T1 - Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares. JF - BMC Musculoskelet Disord Y1 - 2015 A1 - Flynn, Tanya J A1 - Cadzow, Murray A1 - Dalbeth, Nicola A1 - Jones, Peter B A1 - Stamp, Lisa K A1 - Hindmarsh, Jennie Harré A1 - Todd, Alwyn S A1 - Walker, Robert J A1 - Topless, Ruth A1 - Merriman, Tony R KW - Adolescent KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Gout KW - Humans KW - Hyperuricemia KW - Lycopersicon esculentum KW - Male KW - Middle Aged KW - New Zealand KW - Oceanic Ancestry Group KW - Surveys and Questionnaires KW - Uric Acid KW - Young Adult AB -

BACKGROUND: Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels.

METHODS: Two thousand fifty one New Zealanders (of Māori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake.

RESULTS: Seventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20% specifically mentioned tomatoes, the 4(th) most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (β = 0.66 μmolL(-1) increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: β = 0.84 μmolL(-1), P = 0.035; women: β = 0.59 μmolL (-1), P = 0.041).

CONCLUSIONS: While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.

VL - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26286027?dopt=Abstract ER - TY - JOUR T1 - Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE). JF - Am J Hematol Y1 - 2015 A1 - Folsom, Aaron R A1 - Tang, Weihong A1 - Roetker, Nicholas S A1 - Heckbert, Susan R A1 - Cushman, Mary A1 - Pankow, James S KW - African Americans KW - Aged KW - Alleles KW - European Continental Ancestry Group KW - Factor XI KW - Female KW - Gene Expression KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States KW - Venous Thromboembolism AB -

Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (P < 0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African-Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African-Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African-Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African-Americans.

VL - 90 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26260105?dopt=Abstract ER - TY - JOUR T1 - APOL1 Genotype, Kidney and Cardiovascular Disease, and Death in Older Adults. JF - Arterioscler Thromb Vasc Biol Y1 - 2016 A1 - Mukamal, Kenneth J A1 - Tremaglio, Joseph A1 - Friedman, David J A1 - Ix, Joachim H A1 - Kuller, Lewis H A1 - Tracy, Russell P A1 - Pollak, Martin R KW - African Americans KW - Age Factors KW - Aged KW - Albuminuria KW - Apolipoproteins KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cause of Death KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Health Status Disparities KW - Heterozygote KW - Homozygote KW - Humans KW - Incidence KW - Kaplan-Meier Estimate KW - Kidney Diseases KW - Lipoproteins, HDL KW - Male KW - Myocardial Infarction KW - Phenotype KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: We sought to evaluate the cardiovascular impact of coding variants in the apolipoprotein L1 gene APOL1 that protect against trypanosome infection but have been associated with kidney disease among African Americans.

APPROACH AND RESULTS: As part of the Cardiovascular Health Study, a population-based cohort of Americans aged ≥65 years, we genotyped APOL1 polymorphisms rs73885319 and rs71785153 and examined kidney function, subclinical atherosclerosis, and incident cardiovascular disease and death over 13 years of follow-up among 91 African Americans with 2 risk alleles, 707 other African Americans, and 4964 white participants. The high-risk genotype with 2 risk alleles was associated with 2-fold higher levels of albuminuria and lower ankle-brachial indices but similar carotid intima-media thickness among African Americans. Median survival among high-risk African Americans was 9.9 years (95% confidence interval [CI], 8.7-11.9), compared with 13.6 years (95% CI, 12.5-14.3) among other African Americans and 13.3 years (95% CI, 13.0-13.6) among whites (P=0.03). The high-risk genotype was also associated with increased risk for incident myocardial infarction (adjusted hazard ratio 1.8; 95% CI, 1.1-3.0) and mortality (adjusted hazard ratio 1.3; 95% CI 1.0-1.7). Albuminuria and risk for myocardial infarction and mortality were nearly identical between African Americans with 0 to 1 risk alleles and whites.

CONCLUSIONS: APOL1 genotype is associated with albuminuria, subclinical atherosclerosis, incident myocardial infarction, and mortality in older African Americans. African Americans without 2 risk alleles do not differ significantly in risk of myocardial infarction or mortality from whites. APOL1 trypanolytic variants may account for a substantial proportion of the excess risk of chronic disease in African Americans.

VL - 36 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26634651?dopt=Abstract ER - TY - JOUR T1 - Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. JF - Stroke Y1 - 2016 A1 - Cheng, Yu-Ching A1 - Stanne, Tara M A1 - Giese, Anne-Katrin A1 - Ho, Weang Kee A1 - Traylor, Matthew A1 - Amouyel, Philippe A1 - Holliday, Elizabeth G A1 - Malik, Rainer A1 - Xu, Huichun A1 - Kittner, Steven J A1 - Cole, John W A1 - O'Connell, Jeffrey R A1 - Danesh, John A1 - Rasheed, Asif A1 - Zhao, Wei A1 - Engelter, Stefan A1 - Grond-Ginsbach, Caspar A1 - Kamatani, Yoichiro A1 - Lathrop, Mark A1 - Leys, Didier A1 - Thijs, Vincent A1 - Metso, Tiina M A1 - Tatlisumak, Turgut A1 - Pezzini, Alessandro A1 - Parati, Eugenio A A1 - Norrving, Bo A1 - Bevan, Steve A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Slowik, Agnieszka A1 - Lindgren, Arne A1 - Walters, Matthew R A1 - Jannes, Jim A1 - Shen, Jess A1 - Crosslin, David A1 - Doheny, Kimberly A1 - Laurie, Cathy C A1 - Kanse, Sandip M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Mosley, Thomas H A1 - Hopewell, Jemma C A1 - Strauch, Konstantin A1 - Müller-Nurasyid, Martina A1 - Gieger, Christian A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Meisinger, Christine A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Meschia, James F A1 - Seshadri, Sudha A1 - Sharma, Pankaj A1 - Worrall, Bradford A1 - Jern, Christina A1 - Levi, Christopher A1 - Dichgans, Martin A1 - Boncoraglio, Giorgio B A1 - Markus, Hugh S A1 - Debette, Stephanie A1 - Rolfs, Arndt A1 - Saleheen, Danish A1 - Mitchell, Braxton D KW - Adult KW - African Continental Ancestry Group KW - Age of Onset KW - Aged KW - Asian Continental Ancestry Group KW - Brain Ischemia KW - Chromosomes, Human, Pair 10 KW - Computer Simulation KW - DNA, Intergenic KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Serine Endopeptidases KW - Stroke AB -

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.

RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

VL - 47 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract ER - TY - JOUR T1 - Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study. JF - Alzheimers Dement Y1 - 2016 A1 - Kuller, Lewis H A1 - Lopez, Oscar L A1 - Becker, James T A1 - Chang, Yuefang A1 - Newman, Anne B KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Apolipoprotein E4 KW - Brain KW - Cardiovascular Diseases KW - Cognition KW - Dementia KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Neuropsychological Tests KW - Pennsylvania KW - Risk Factors KW - Walking AB -

INTRODUCTION: Increasing life expectancy has resulted in a larger population of older individuals at risk of dementia.

METHODS: The Cardiovascular Health Study-Cognition Study followed 532 participants from 1998-99 (mean age 79) to 2013 (mean age 93) for death and dementia.

RESULTS: Risk of death was determined by extent of coronary artery calcium, high-sensitivity cardiac troponin, brain natriuretic peptide, and white matter grade. Significant predictors of dementia were age, apolipoprotein-E4, vocabulary raw score, hippocampal volume, ventricular size, cognitive performance, and number of blocks walked. By 2013, 160 of 532 were alive, including 19 cognitively normal. Those with normal cognition had higher grade education, better cognition test scores, greater hippocampal volume, faster gait speed, and number of blocks walked as compared with survivors who were demented.

DISCUSSION: Few survived free of dementia and disability. Prevention and delay of cognitive decline for this older population is an imperative.

VL - 12 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26519786?dopt=Abstract ER - TY - JOUR T1 - Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study. JF - Hum Genet Y1 - 2017 A1 - Lindström, Sara A1 - Germain, Marine A1 - Crous-Bou, Marta A1 - Smith, Erin N A1 - Morange, Pierre-Emmanuel A1 - van Hylckama Vlieg, Astrid A1 - de Haan, Hugoline G A1 - Chasman, Daniel A1 - Ridker, Paul A1 - Brody, Jennifer A1 - de Andrade, Mariza A1 - Heit, John A A1 - Tang, Weihong A1 - DeVivo, Immaculata A1 - Grodstein, Francine A1 - Smith, Nicholas L A1 - Tregouet, David A1 - Kabrhel, Christopher KW - Adult KW - Body Mass Index KW - Case-Control Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Logistic Models KW - Male KW - Mendelian Randomization Analysis KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Venous Thromboembolism AB -

Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

VL - 136 IS - 7 ER - TY - JOUR T1 - Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. JF - PLoS One Y1 - 2017 A1 - Mozaffarian, Dariush A1 - Dashti, Hassan S A1 - Wojczynski, Mary K A1 - Chu, Audrey Y A1 - Nettleton, Jennifer A A1 - Männistö, Satu A1 - Kristiansson, Kati A1 - Reedik, Mägi A1 - Lahti, Jari A1 - Houston, Denise K A1 - Cornelis, Marilyn C A1 - van Rooij, Frank J A A1 - Dimitriou, Maria A1 - Kanoni, Stavroula A1 - Mikkilä, Vera A1 - Steffen, Lyn M A1 - de Oliveira Otto, Marcia C A1 - Qi, Lu A1 - Psaty, Bruce A1 - Djoussé, Luc A1 - Rotter, Jerome I A1 - Harald, Kennet A1 - Perola, Markus A1 - Rissanen, Harri A1 - Jula, Antti A1 - Krista, Fischer A1 - Mihailov, Evelin A1 - Feitosa, Mary F A1 - Ngwa, Julius S A1 - Xue, Luting A1 - Jacques, Paul F A1 - Perälä, Mia-Maria A1 - Palotie, Aarno A1 - Liu, Yongmei A1 - Nalls, Nike A A1 - Ferrucci, Luigi A1 - Hernandez, Dena A1 - Manichaikul, Ani A1 - Tsai, Michael Y A1 - Kiefte-de Jong, Jessica C A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rallidis, Loukianos A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Buring, Julie E A1 - Lehtimäki, Terho A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lemaitre, Rozenn A1 - Salomaa, Veikko A1 - Knekt, Paul A1 - Metspalu, Andres A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Eriksson, Johan G A1 - Kritchevsky, Stephen B A1 - Bandinelli, Stefania A1 - Siscovick, David A1 - Franco, Oscar H A1 - Deloukas, Panos A1 - Dedoussis, George A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Tanaka, Toshiko KW - Adult KW - Aged KW - Cohort Studies KW - Docosahexaenoic Acids KW - Eicosapentaenoic Acid KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Seafood KW - United States AB -

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

VL - 12 IS - 12 ER - TY - JOUR T1 - Phenotype-Specific Association of Single-Nucleotide Polymorphisms with Heart Failure and Preserved Ejection Fraction: a Genome-Wide Association Analysis of the Cardiovascular Health Study. JF - J Cardiovasc Transl Res Y1 - 2017 A1 - Kao, David P A1 - Stevens, Laura M A1 - Hinterberg, Michael A A1 - Görg, Carsten KW - Aged KW - Computational Biology KW - Databases, Genetic KW - European Continental Ancestry Group KW - Female KW - Gene Expression Profiling KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Failure KW - Humans KW - Male KW - Oligonucleotide Array Sequence Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Predictive Value of Tests KW - Prognosis KW - Proteoglycans KW - Receptors, Transforming Growth Factor beta KW - Risk Assessment KW - Risk Factors KW - Stroke Volume KW - United States AB -

Little is known about genetics of heart failure with preserved ejection fraction (HFpEF) in part because of the many comorbidities in this population. To identify single-nucleotide polymorphisms (SNPs) associated with HFpEF, we analyzed phenotypic and genotypic data from the Cardiovascular Health Study, which profiled patients using a 50,000 SNP array. Results were explored using novel SNP- and gene-centric tools. We performed analyses to determine whether some SNPs were relevant only in certain phenotypes. Among 3804 patients, 7 clinical factors and 9 SNPs were significantly associated with HFpEF; the most notable of which was rs6996224, a SNP associated with transforming growth factor-beta receptor 3. Most SNPs were associated with HFpEF only in the absence of a clinical predictor. Significant SNPs represented genes involved in myocyte proliferation, transforming growth factor-beta/erbB signaling, and extracellular matrix formation. These findings suggest that genetic factors may be more important in some phenotypes than others.

VL - 10 IS - 3 ER - TY - JOUR T1 - Short telomere length is associated with impaired cognitive performance in European ancestry cohorts. JF - Transl Psychiatry Y1 - 2017 A1 - Hägg, S A1 - Zhan, Y A1 - Karlsson, R A1 - Gerritsen, L A1 - Ploner, A A1 - van der Lee, S J A1 - Broer, L A1 - Deelen, J A1 - Marioni, R E A1 - Wong, A A1 - Lundquist, A A1 - Zhu, G A1 - Hansell, N K A1 - Sillanpää, E A1 - Fedko, I O A1 - Amin, N A A1 - Beekman, M A1 - de Craen, A J M A1 - Degerman, S A1 - Harris, S E A1 - Kan, K-J A1 - Martin-Ruiz, C M A1 - Montgomery, G W A1 - Adolfsson, A N A1 - Reynolds, C A A1 - Samani, N J A1 - Suchiman, H E D A1 - Viljanen, A A1 - von Zglinicki, T A1 - Wright, M J A1 - Hottenga, J-J A1 - Boomsma, D I A1 - Rantanen, T A1 - Kaprio, J A A1 - Nyholt, D R A1 - Martin, N G A1 - Nyberg, L A1 - Adolfsson, R A1 - Kuh, D A1 - Starr, J M A1 - Deary, I J A1 - Slagboom, P E A1 - van Duijn, C M A1 - Codd, V A1 - Pedersen, N L KW - Adult KW - Aged KW - Apolipoprotein E4 KW - Cognitive Dysfunction KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Carrier Screening KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Neuropsychological Tests KW - Psychometrics KW - Statistics as Topic KW - Telomere AB -

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (β=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (β=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (β=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

VL - 7 IS - 4 ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

VL - 51 IS - 6 ER - TY - JOUR T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JF - Nat Commun Y1 - 2019 A1 - Kilpeläinen, Tuomas O A1 - Bentley, Amy R A1 - Noordam, Raymond A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Jakupović, Hermina A1 - Chasman, Daniel I A1 - Manning, Alisa A1 - Ntalla, Ioanna A1 - Aschard, Hugues A1 - Brown, Michael R A1 - de Las Fuentes, Lisa A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Feitosa, Mary F A1 - Kho, Minjung A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Wang, Heming A1 - Wang, Zhe A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Li, Changwei A1 - Lohman, Kurt K A1 - Marten, Jonathan A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Graff, Mariaelisa A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Zhao, Jing Hua A1 - Kraja, Aldi T A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Rueedi, Rico A1 - Stringham, Heather M A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Verweij, Niek A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Li, Xiaoyin A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Brumat, Marco A1 - Cade, Brian A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Concas, Maria Pina A1 - Connell, John A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Demirkan, Ayse A1 - Ding, Jingzhong A1 - Eaton, Charles B A1 - Faul, Jessica D A1 - Friedlander, Yechiel A1 - Gabriel, Kelley P A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven C A1 - Ikram, M Arfan A1 - Jonas, Jost B A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Leander, Karin A1 - Lemaitre, Rozenn N A1 - Lewis, Cora E A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Mägi, Reedik A1 - Manichaikul, Ani A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nang, Ei-Ei Khaing A1 - Nelson, Christopher P A1 - Nona, Sotoodehnia A1 - Norris, Jill M A1 - Nwuba, Chiamaka Vivian A1 - O'Connell, Jeff A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poveda, Alaitz A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Risch, Neil A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schreiner, Pamela J A1 - Scott, Robert A A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Starr, John M A1 - Sternfeld, Barbara A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - van der Ende, M Yldau A1 - van Heemst, Diana A1 - Voortman, Trudy A1 - Waldenberger, Melanie A1 - Wennberg, Patrik A1 - Wilson, Gregory A1 - Xiang, Yong-Bing A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - van Vliet-Ostaptchouk, Jana V A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wang, Ya X A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Evans, Michele K A1 - Franks, Paul W A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Liu, Yongmei A1 - North, Kari E A1 - Pereira, Alexandre C A1 - Ridker, Paul M A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - Fox, Ervin R A1 - Kardia, Sharon L R A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Redline, Susan A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Kooperberg, Charles B A1 - Gauderman, W James A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Fornage, Myriam A1 - Cupples, L Adrienne A1 - Rotimi, Charles N A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Loos, Ruth J F KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Brazil KW - Calcium-Binding Proteins KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Exercise KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Hispanic Americans KW - Humans KW - LIM-Homeodomain Proteins KW - Lipid Metabolism KW - Lipids KW - Male KW - Membrane Proteins KW - Microtubule-Associated Proteins KW - Middle Aged KW - Muscle Proteins KW - Nerve Tissue Proteins KW - Transcription Factors KW - Triglycerides KW - Young Adult AB -

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

VL - 10 IS - 1 ER - TY - JOUR T1 - Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. JF - PLoS One Y1 - 2020 A1 - Hahn, Julie A1 - Fu, Yi-Ping A1 - Brown, Michael R A1 - Bis, Joshua C A1 - de Vries, Paul S A1 - Feitosa, Mary F A1 - Yanek, Lisa R A1 - Weiss, Stefan A1 - Giulianini, Franco A1 - Smith, Albert Vernon A1 - Guo, Xiuqing A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Chen, Yii-Der Ida A1 - Franco, Oscar H A1 - Grove, Megan A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Hwang, Shih-Jen A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Markus, Marcello R P A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Yao, Jie A1 - Chasman, Daniel I A1 - Dörr, Marcus A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Post, Wendy A1 - Psaty, Bruce M A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Morrison, Alanna C KW - Aging KW - Coronary Artery Disease KW - Cross-Sectional Studies KW - Europe KW - European Continental Ancestry Group KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

VL - 15 IS - 11 ER -