%0 Journal Article %J Am J Hypertens %D 2002 %T Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events. %A Hindorff, Lucia A %A Heckbert, Susan R %A Tracy, Russell %A Tang, Zhonghua %A Psaty, Bruce M %A Edwards, Karen L %A Siscovick, David S %A Kronmal, Richard A %A Nazar-Stewart, Valle %K African Continental Ancestry Group %K Aged %K Blood Pressure %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Gene Frequency %K Humans %K Hypertension %K Male %K Polymorphism, Genetic %K Receptor, Angiotensin, Type 1 %K Receptors, Angiotensin %K United States %X

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.

%B Am J Hypertens %V 15 %P 1050-6 %8 2002 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/12460700?dopt=Abstract %R 10.1016/s0895-7061(02)03063-7 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2003 %T Alcohol consumption and carotid atherosclerosis in older adults: the Cardiovascular Health Study. %A Mukamal, Kenneth J %A Kronmal, Richard A %A Mittleman, Murray A %A O'Leary, Daniel H %A Polak, Joseph F %A Cushman, Mary %A Siscovick, David S %K Aged %K Alcohol Drinking %K Cardiovascular Diseases %K Carotid Artery Diseases %K Cross-Sectional Studies %K Female %K Health Surveys %K Humans %K Longitudinal Studies %K Male %K Prospective Studies %X

OBJECTIVE: The association of alcohol use with atherosclerosis is inconsistent in previous studies.

METHODS AND RESULTS: For the Cardiovascular Health Study, 5888 adults aged 65 years and older underwent a standardized interview and examination. They reported beer, wine, and liquor use individually and underwent B-mode ultrasonography to determine internal and common carotid intima-media thickness (IMT). We compared composite carotid IMT values cross-sectionally using linear regression to adjust for demographic and clinical characteristics. Among 4247 participants free of cardiovascular disease, consumers of 1 to 6 drinks per week had 0.07+/-0.04-mm lower composite IMT and consumers of 14 or more drinks per week had 0.07+/-0.05-mm higher IMT than abstainers (P quadratic trend=0.02). We found similar relationships using internal and common carotid thickness measures and among men and women. The higher IMT associated with heavier alcohol use was particularly strong among 1592 participants with confirmed cardiovascular disease (0.24+/-0.09 mm greater than abstainers). Controlling for HDL cholesterol levels reduced the effect on composite IMT among consumers of 1 to 6 drinks per week by 22%.

CONCLUSIONS: Relative to older adults who abstain from alcohol, consumption of 1 to 6 drinks per week had an inverse association with carotid atherosclerosis whereas consumption of 14 or more drinks had a positive association.

%B Arterioscler Thromb Vasc Biol %V 23 %P 2252-9 %8 2003 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/14563651?dopt=Abstract %R 10.1161/01.ATV.0000101183.58453.39 %0 Journal Article %J Circulation %D 2003 %T Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. %A Heckbert, Susan R %A Hindorff, Lucia A %A Edwards, Karen L %A Psaty, Bruce M %A Lumley, Thomas %A Siscovick, David S %A Tang, Zhonghua %A Durda, J Peter %A Kronmal, Richard A %A Tracy, Russell P %K African Continental Ancestry Group %K Aged %K Alleles %K Brain Ischemia %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Coronary Disease %K European Continental Ancestry Group %K Follow-Up Studies %K Gene Frequency %K Humans %K Incidence %K Linkage Disequilibrium %K Polymorphism, Genetic %K Receptors, Adrenergic, beta-2 %K Risk Assessment %K Stroke %K United States %X

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.

%B Circulation %V 107 %P 2021-4 %8 2003 Apr 22 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/12682000?dopt=Abstract %R 10.1161/01.CIR.0000065231.07729.92 %0 Journal Article %J Circulation %D 2003 %T Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. %A Mozaffarian, Dariush %A Lemaitre, Rozenn N %A Kuller, Lewis H %A Burke, Gregory L %A Tracy, Russell P %A Siscovick, David S %K Aged %K Animals %K Arrhythmias, Cardiac %K Diet %K Eating %K Fatty Acids, Omega-3 %K Female %K Fishes %K Humans %K Male %K Myocardial Infarction %K Myocardial Ischemia %K Prospective Studies %K Risk %K Tuna %X

BACKGROUND: Few studies have examined associations of fish consumption with ischemic heart disease (IHD) risk among older adults or how different types of fish meals relate to IHD risk.

METHODS AND RESULTS: In a population-based prospective cohort study, usual fish consumption was ascertained at baseline among 3910 adults aged > or =65 years and free of known cardiovascular disease in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. Over 9.3 years' mean follow-up, there were 247 IHD deaths (including 148 arrhythmic deaths) and 363 incident nonfatal myocardial infarctions (MIs). After adjustment for potential confounders, consumption of tuna or other broiled or baked fish was associated with lower risk of total IHD death (P for trend=0.001) and arrhythmic IHD death (P=0.001) but not nonfatal MI (P=0.44), with 49% lower risk of total IHD death and 58% lower risk of arrhythmic IHD death among persons consuming tuna/other fish 3 or more times per week compared with less than once per month. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of total IHD death, arrhythmic IHD death, or nonfatal MI but rather with trends toward higher risk.

CONCLUSIONS: Among adults aged > or =65 years, modest consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower risk of IHD death, especially arrhythmic IHD death. Cardiac benefits of fish consumption may vary depending on the type of fish meal consumed.

%B Circulation %V 107 %P 1372-7 %8 2003 Mar 18 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/12642356?dopt=Abstract %R 10.1161/01.cir.0000055315.79177.16 %0 Journal Article %J JAMA %D 2003 %T Cereal, fruit, and vegetable fiber intake and the risk of cardiovascular disease in elderly individuals. %A Mozaffarian, Dariush %A Kumanyika, Shiriki K %A Lemaitre, Rozenn N %A Olson, Jean L %A Burke, Gregory L %A Siscovick, David S %K Aged %K Cardiovascular Diseases %K Dietary Fiber %K Edible Grain %K Female %K Fruit %K Humans %K Male %K Nutrition Assessment %K Prospective Studies %K Risk %K Vegetables %X

CONTEXT: People older than 65 years are the fastest-growing segment of the population and account for the majority of cardiovascular disease (CVD) morbidity, mortality, and health care expenditures. Additionally, the influence of dietary habits on risk may be less pronounced in elderly persons, when atherosclerosis is more advanced. However, few data address the influence of diet on CVD risk in this population.

OBJECTIVE: To determine whether fiber consumption from fruit, vegetable, and cereal sources (including whole grains and bran) is associated with incident CVD in elderly persons.

DESIGN: Prospective cohort study conducted from 1989 to June 2000.

SETTING AND PARTICIPANTS: Population-based, multicenter study among 3588 men and women aged 65 years or older and free of known CVD at baseline in 1989-1990. Usual dietary fiber consumption was assessed at baseline (mean participant age, 72 years) using a 99-item food frequency questionnaire.

MAIN OUTCOME MEASURE: Incident CVD (combined stroke, ischemic heart disease death, and nonfatal myocardial infarction).

RESULTS: During 8.6 years mean follow-up, there were 811 incident CVD events. After adjustment for age, sex, education, diabetes, ever smoking, pack-years of smoking, daily physical activity, exercise intensity, alcohol intake, and fruit and vegetable fiber consumption, cereal fiber consumption was inversely associated with incident CVD (P for trend =.02), with 21% lower risk (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.62-0.99) in the highest quintile of intake, compared with the lowest quintile. In similar analyses, neither fruit fiber intake (P for trend =.98) nor vegetable fiber intake (P for trend =.95) were associated with incident CVD. When CVD events were separately evaluated, higher cereal fiber intake was associated with lower risk of total stroke and ischemic stroke and a trend toward lower risk of ischemic heart disease death. In a post hoc analysis, dark breads such as wheat, rye, or pumpernickel were associated with a lower risk of incident CVD (HR, 0.76; 95% CI, 0.64-0.90) rather than cereal fiber from other sources.

CONCLUSIONS: Cereal fiber consumption late in life is associated with lower risk of incident CVD, supporting recommendations for elderly individuals to increase consumption of dietary cereal fiber.

%B JAMA %V 289 %P 1659-66 %8 2003 Apr 02 %G eng %N 13 %1 https://www.ncbi.nlm.nih.gov/pubmed/12672734?dopt=Abstract %R 10.1001/jama.289.13.1659 %0 Journal Article %J Am J Clin Nutr %D 2003 %T n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. %A Lemaitre, Rozenn N %A King, Irena B %A Mozaffarian, Dariush %A Kuller, Lewis H %A Tracy, Russell P %A Siscovick, David S %K Aged %K alpha-Linolenic Acid %K Biomarkers %K Case-Control Studies %K Cohort Studies %K Coronary Disease %K Dietary Supplements %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Fatty Acids, Omega-3 %K Female %K Fish Oils %K Humans %K Incidence %K Male %K Myocardial Infarction %K Odds Ratio %K Phospholipids %K Prevalence %K Prospective Studies %K Risk Factors %X

BACKGROUND: Little is known about the relation of the dietary intake of n-3 polyunsaturated fatty acids, ie, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fatty fish and alpha-linolenic acid from vegetable oils, with ischemic heart disease among older adults.

OBJECTIVE: We investigated the associations of plasma phospholipid concentrations of DHA, EPA, and alpha-linolenic acid as biomarkers of intake with the risk of incident fatal ischemic heart disease and incident nonfatal myocardial infarction in older adults.

DESIGN: We conducted a case-control study nested in the Cardiovascular Health Study, a cohort study of adults aged > or = 65 y. Cases experienced incident fatal myocardial infarction and other ischemic heart disease death (n = 54) and incident nonfatal myocardial infarction (n = 125). Matched controls were randomly selected (n = 179). We measured plasma phospholipid concentrations of n-3 polyunsaturated fatty acids in blood samples drawn approximately 2 y before the event.

RESULTS: A higher concentration of combined DHA and EPA was associated with a lower risk of fatal ischemic heart disease, and a higher concentration of alpha-linolenic acid with a tendency to lower risk, after adjustment for risk factors [odds ratio: 0.32 (95% CI: 0.13, 0.78; P = 0.01) and 0.52 (0.24, 1.15; P = 0.1), respectively]. In contrast, n-3 polyunsaturated fatty acids were not associated with nonfatal myocardial infarction.

CONCLUSIONS: Higher combined dietary intake of DHA and EPA, and possibly alpha-linolenic acid, may lower the risk of fatal ischemic heart disease in older adults. The association of n-3 polyunsaturated fatty acids with fatal ischemic heart disease, but not with nonfatal myocardial infarction, is consistent with possible antiarrhythmic effects of these fatty acids.

%B Am J Clin Nutr %V 77 %P 319-25 %8 2003 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/12540389?dopt=Abstract %R 10.1093/ajcn/77.2.319 %0 Journal Article %J Ophthalmology %D 2003 %T The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study. %A Wong, Tien Yin %A Klein, Ronald %A Sharrett, A Richey %A Manolio, Teri A %A Hubbard, Larry D %A Marino, Emily K %A Kuller, Lewis %A Burke, Gregory %A Tracy, Russell P %A Polak, Joseph F %A Gottdiener, John S %A Siscovick, David S %K Aged %K Aged, 80 and over %K Blood Pressure %K Coronary Artery Disease %K Cross-Sectional Studies %K Female %K Humans %K Hypertension %K Male %K Prevalence %K Retinal Diseases %K Retinal Vessels %K Risk Factors %K United States %X

PURPOSE: To describe the prevalence of retinal microvascular characteristics and their associations with atherosclerosis in elderly, nondiabetic persons.

DESIGN AND PARTICIPANTS: Population-based, cross-sectional study comprising 2050 men and women aged 69 to 97 years without diabetes, living in four communities.

METHODS: Participants underwent retinal photography and standardized grading of retinal microvascular characteristics, including retinopathy (e.g., microaneurysms, retinal hemorrhages), focal arteriolar narrowing, and arteriovenous nicking. In addition, calibers of retinal arterioles and venules were measured on digitized photographs to obtain an estimate of generalized arteriolar narrowing. Atherosclerosis and its risk factors were obtained from clinical examination and laboratory investigations.

MAIN OUTCOME MEASURES: Prevalence of retinal microvascular abnormalities and their associations with measures of atherosclerosis.

RESULTS: The prevalence of retinal microvascular abnormalities was 8.3% for retinopathy, 9.6% for focal arteriolar narrowing, and 7.7% for arteriovenous nicking. All retinal lesions were associated with hypertension (odds ratios [OR] were 1.8 for retinopathy, 2.1 for focal arteriolar narrowing, 1.5 for arteriovenous nicking, and 1.7 for generalized arteriolar narrowing). After controlling for age, gender, race, mean arterial blood pressure, and antihypertensive medication use, retinopathy was associated with prevalent coronary heart disease (OR, 1.7), prevalent myocardial infarction (OR, 1.7), prevalent stroke (OR, 2.0), presence of carotid artery plaque (OR, 1.9), and increased intima-media thickness of the common carotid (OR, 2.3; fourth vs. first quartile) and internal carotid (OR, 1.8; fourth vs. first quartile) arteries. In contrast, focal arteriolar narrowing, arteriovenous nicking, and generalized arteriolar narrowing were not associated with any measures of atherosclerosis.

CONCLUSIONS: Retinal microvascular abnormalities are common in older persons without diabetes and are related to hypertension. Retinopathy is associated with prevalent coronary heart disease, stroke, and carotid artery thickening, but focal and generalized arteriolar narrowing and arteriovenous nicking are not related to most measures of atherosclerosis. These data suggest that retinal microvascular abnormalities reflect processes associated with hypertension but distinct from atherosclerosis.

%B Ophthalmology %V 110 %P 658-66 %8 2003 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12689883?dopt=Abstract %R 10.1016/S0161-6420(02)01931-0 %0 Journal Article %J JAMA %D 2003 %T Prospective study of alcohol consumption and risk of dementia in older adults. %A Mukamal, Kenneth J %A Kuller, Lewis H %A Fitzpatrick, Annette L %A Longstreth, W T %A Mittleman, Murray A %A Siscovick, David S %K Aged %K Alcohol Drinking %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Case-Control Studies %K Dementia %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk %X

CONTEXT: Alcohol consumption has been associated with complex changes in cerebral vasculature and structure in older adults. How alcohol consumption affects the incidence of dementia is less clear.

OBJECTIVE: To determine the prospective relationship of alcohol consumption and risk of dementia among older adults.

DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study of 373 cases with incident dementia and 373 controls who were among 5888 adults aged 65 years and older who participated in the Cardiovascular Health Study, a prospective, population-based cohort study in 4 US communities. The controls were frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in this study underwent magnetic resonance imaging (MRI) of the brain and cognitive testing between 1992 and 1994 and were followed up until 1999.

MAIN OUTCOME MEASURES: Odds of incident dementia, ascertained by detailed neurological and neuropsychological examinations according to average alcohol consumption, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the date of the MRI.

RESULTS: Compared with abstention, the adjusted odds for dementia among those whose weekly alcohol consumption was less than 1 drink were 0.65 (95% confidence interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95% CI, 0.27-0.77); 7 to 13 drinks, 0.69 (95% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95% CI, 0.60-2.49; P for quadratic term =.001). A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E epsilon4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia.

CONCLUSIONS: Compared with abstention, consumption of 1 to 6 drinks weekly is associated with a lower risk of incident dementia among older adults.

%B JAMA %V 289 %P 1405-13 %8 2003 Mar 19 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/12636463?dopt=Abstract %R 10.1001/jama.289.11.1405 %0 Journal Article %J Atherosclerosis %D 2004 %T Alcohol consumption and inflammatory markers in older adults: the Cardiovascular Health Study. %A Mukamal, Kenneth J %A Cushman, Mary %A Mittleman, Murray A %A Tracy, Russell P %A Siscovick, David S %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Apolipoproteins E %K C-Reactive Protein %K Coronary Artery Disease %K Female %K Fibrinogen %K Geriatric Assessment %K Humans %K Inflammation Mediators %K Leukocyte Count %K Logistic Models %K Longitudinal Studies %K Male %K Probability %K Prospective Studies %K Risk Assessment %K Sensitivity and Specificity %K Severity of Illness Index %X

OBJECTIVE: We sought to determine the relation of alcohol intake and systemic inflammation in a population-based sample of older adults.

METHODS AND RESULTS: As part of the Cardiovascular Health Study (CHS), 5865 adults aged 65 years and older reported their intake of beer, wine, and liquor. We determined white blood cell count (WBC), factor VIII coagulant activity (factor VIIIc), and levels of C-reactive protein (CRP), fibrinogen, and albumin as markers of systemic inflammation. Among participants without confirmed cardiovascular disease, alcohol consumption was inversely associated with WBC, factor VIIIc, and fibrinogen level, and positively associated with albumin concentration in multivariate analyses. We found no consistent modification of these results by sex, obesity, or beverage type. The relation of alcohol use and CRP levels was significantly modified by apoE genotype (P interaction 0.03), with a positive association among participants with an apoE4 allele (P = 0.05), but a trend toward an inverse association among those without an apoE4 allele (P = 0.15).

CONCLUSIONS: Alcohol intake is associated with lower levels of inflammatory markers in older adults free of cardiovascular disease.

%B Atherosclerosis %V 173 %P 79-87 %8 2004 Mar %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15177126?dopt=Abstract %R 10.1016/j.atherosclerosis.2003.10.011 %0 Journal Article %J Circulation %D 2004 %T Fish intake and risk of incident atrial fibrillation. %A Mozaffarian, Dariush %A Psaty, Bruce M %A Rimm, Eric B %A Lemaitre, Rozenn N %A Burke, Gregory L %A Lyles, Mary F %A Lefkowitz, David %A Siscovick, David S %K Aged %K Animals %K Atrial Fibrillation %K Cardiotonic Agents %K Cohort Studies %K Cooking %K Diet %K Dietary Fats %K Fatty Acids, Omega-3 %K Fish Oils %K Fishes %K Follow-Up Studies %K Humans %K Incidence %K Massachusetts %K Proportional Hazards Models %K Prospective Studies %K Risk %K Seafood %K Tuna %X

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated.

METHODS AND RESULTS: In a prospective, population-based cohort of 4815 adults > or =age 65 years, usual dietary intake was assessed at baseline in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years' follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28% lower risk with intake 1 to 4 times per week (HR=0.72, 95% CI=0.58 to 0.91, P=0.005), and 31% lower risk with intake > or =5 times per week (HR=0.69, 95% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF.

CONCLUSIONS: Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia.

%B Circulation %V 110 %P 368-73 %8 2004 Jul 27 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15262826?dopt=Abstract %R 10.1161/01.CIR.0000138154.00779.A5 %0 Journal Article %J J Am Coll Cardiol %D 2004 %T Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. %A Drazner, Mark H %A Rame, J Eduardo %A Marino, Emily K %A Gottdiener, John S %A Kitzman, Dalane W %A Gardin, Julius M %A Manolio, Teri A %A Dries, Daniel L %A Siscovick, David S %K Aged %K Body Surface Area %K Coronary Artery Disease %K Diastole %K Echocardiography %K Electrocardiography %K Female %K Follow-Up Studies %K Heart Ventricles %K Humans %K Hypertrophy, Left Ventricular %K Longitudinal Studies %K Male %K Multivariate Analysis %K Prospective Studies %K Risk Factors %K Sensitivity and Specificity %K Statistics as Topic %K Stroke Volume %K Ventricular Dysfunction, Left %X

OBJECTIVES: Our aim in this study was to determine whether increased left ventricular mass (LVM) is a risk factor for the development of a reduced left ventricular ejection fraction (LVEF).

BACKGROUND: Prior studies have shown that increased LVM is a risk factor for heart failure but not whether it is a risk factor for a low LVEF.

METHODS: As part of the Cardiovascular Health Study, a prospective population-based longitudinal study, we performed echocardiograms upon participant enrollment and again at follow-up of 4.9 +/- 0.14 years. In the present analysis, we identified 3,042 participants who had at baseline a normal LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram), and at follow-up a measurable LVEF. The frequency of the development of a qualitatively depressed LVEF on two-dimensional echocardiography, corresponding approximately to an LVEF <55%, was analyzed by quartiles of baseline LVM. Multivariable regression determined whether LVM was independently associated with the development of depressed LVEF.

RESULTS: Baseline quartile of echocardiographic LVM indexed to body surface area was associated with development of a depressed LVEF (4.8% in quartile 1, 4.4% in quartile 2, 7.5% in quartile 3, and 14.1% in quartile 4 [p < 0.001]). A similar relationship was seen in the subgroup of participants without myocardial infarction (p < 0.001). In multivariable regression that adjusted for confounders, both baseline echocardiographic (p < 0.001) and electrocardiographic (p < 0.001) LVM remained associated with development of depressed LVEF.

CONCLUSIONS: Increased LVM as assessed by electrocardiography or echocardiography is an independent risk factor for the development of depressed LVEF.

%B J Am Coll Cardiol %V 43 %P 2207-15 %8 2004 Jun 16 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15193681?dopt=Abstract %R 10.1016/j.jacc.2003.11.064 %0 Journal Article %J Am J Geriatr Cardiol %D 2004 %T Lifestyles of older adults: can we influence cardiovascular risk in older adults? %A Mozaffarian, Dariush %A Fried, Linda P %A Burke, Gregory L %A Fitzpatrick, Annette %A Siscovick, David S %K Aged %K Alcohol Drinking %K Cardiovascular Diseases %K Diet Fads %K Dietary Fiber %K Exercise %K Feeding Behavior %K Humans %K Life Style %K Predictive Value of Tests %K Risk Factors %K Smoking %X

Influences of lifestyle habits on cardiovascular disease risk among older adults are not well established. The authors present evidence from the Cardiovascular Health Study that dietary, physical activity, and smoking habits assessed late in life are associated with cardiovascular disease risk among adults aged 65 years or older. Persons consuming fatty fish twice per week had a 47% lower risk of coronary death compared with those who consumed fatty fish less than once per month, while cereal fiber intake (about two whole-grain bread slices per day) was associated with a 14% lower risk of myocardial infarction or stroke. Modest alcohol intake (1-6 drinks per week) predicted the fewest subclinical cerebrovascular abnormalities. Compared with little activity, moderate and high leisure-time activity predicted 28% and 44% lower mortality, respectively, while compared with nonexercisers, low, moderate, and high exercise intensity predicted 30%, 37%, and 53% more years of healthy life, respectively. Former and current smokers had 25% and 44% fewer years of healthy life than those who never smoked; lifetime smoking (pack-years) predicted higher mortality. Clinical practice and public health implications, gaps in knowledge, and future research directions are summarized.

%B Am J Geriatr Cardiol %V 13 %P 153-60 %8 2004 May-Jun %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/15133418?dopt=Abstract %R 10.1111/j.1076-7460.2004.02122.x %0 Journal Article %J J Am Soc Nephrol %D 2004 %T Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. %A Seliger, Stephen L %A Siscovick, David S %A Stehman-Breen, Catherine O %A Gillen, Daniel L %A Fitzpatrick, Annette %A Bleyer, Anthony %A Kuller, Lew H %K Aged %K Alzheimer Disease %K Cardiovascular Diseases %K Creatinine %K Dementia %K Dementia, Vascular %K Female %K Humans %K Kidney %K Kidney Diseases %K Male %K Muscles %K Proportional Hazards Models %X

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia (n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr > or = 1.3 mg/dl for women and > or = 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37% increased risk of dementia (95% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26% increased risk (95% CI = 1.02 to 1.60). These associations were present only among the 84% of older adults who reported good-excellent health. Among those in good-excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good-excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.

%B J Am Soc Nephrol %V 15 %P 1904-11 %8 2004 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/15213280?dopt=Abstract %R 10.1097/01.asn.0000131529.60019.fa %0 Journal Article %J J Am Geriatr Soc %D 2004 %T Self-reported alcohol consumption and falls in older adults: cross-sectional and longitudinal analyses of the cardiovascular health study. %A Mukamal, Kenneth J %A Mittleman, Murray A %A Longstreth, W T %A Newman, Anne B %A Fried, Linda P %A Siscovick, David S %K Accidental Falls %K Aged %K Alcohol Drinking %K Chi-Square Distribution %K Cross-Sectional Studies %K Female %K Humans %K Longitudinal Studies %K Male %K Regression Analysis %K Risk Factors %K Self Disclosure %K United States %X

OBJECTIVES: To assess the cross-sectional and longitudinal associations between alcohol consumption and risk of falls in older adults.

DESIGN: Cross-sectional and longitudinal analyses.

SETTING: Four U.S. communities.

PARTICIPANTS: A total of 5,841 older adults enrolled in the Cardiovascular Health Study, an ongoing, population-based, prospective cohort study, participated.

MEASUREMENTS: Self-reported alcohol consumption at baseline, self-reported frequent falls at baseline, and the 4-year risk of falls of participants who denied frequent falls at baseline.

RESULTS: Cross-sectional analysis indicated an apparent inverse association between alcohol consumption and risk of frequent falls (adjusted odds ratio in consumers of 14 or more drinks per week=0.41; 95% confidence interval (CI)=0.14-1.17; P for trend=.06), but longitudinal analysis indicated a similar 4-year risk of falls in abstainers and light to moderate drinkers but a 25% higher risk in consumers of 14 or more drinks per week (95% CI=3-52%; P for trend=.07). Similar results were found in analyses stratified by age, sex, race, and physical activity.

CONCLUSION: Consumption of 14 or more drinks per week is associated with an increased risk of subsequent falls in older adults. Cross-sectional studies may fail to identify this risk of heavier drinking, perhaps because older adults at risk for falls decrease their alcohol use over time or because heavier drinkers at risk for falls tend not to enroll in cohort studies. However, because this study relied upon annual reporting of falls, further prospective studies should be conducted to confirm these findings.

%B J Am Geriatr Soc %V 52 %P 1174-9 %8 2004 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/15209658?dopt=Abstract %R 10.1111/j.1532-5415.2004.52318.x %0 Journal Article %J Am J Geriatr Cardiol %D 2004 %T Traditional and novel risk factors in older adults: cardiovascular risk assessment late in life. %A Mukamal, Kenneth J %A Kronmal, Richard A %A Tracy, Russell P %A Cushman, Mary %A Siscovick, David S %K Aged %K Blood Coagulation Factors %K Cardiovascular Diseases %K Cohort Studies %K Diabetes Complications %K Female %K Genetic Predisposition to Disease %K Humans %K Hypertension %K Infections %K Inflammation %K Lipids %K Longitudinal Studies %K Male %K Obesity %K Predictive Value of Tests %K Risk Factors %K Smoking %K United States %X

As a population-based, longitudinal study of nearly 6000 older American adults, the Cardiovascular Health Study provides an excellent opportunity to assess the roles of traditional and novel cardiovascular risk factors in the development of coronary heart disease. Cardiovascular Health Study investigators have analyzed both traditional risk factors, such as diabetes, hypertension, and smoking, and new risk factors, such as hemostatic factors, inflammatory markers, exposure to infectious agents, and genetic determinants. These analyses have led to several important conclusions. First, older adults without previous cardiovascular events have a tremendous burden of subclinical vascular disease, which may change how physicians view risk factor modification in this age group. Second, some traditional cardiovascular risk factors lose importance as predictors of cardiovascular disease among older adults. Third, even modest elevations in fasting blood glucose or systolic blood pressure-below the levels used to define diabetes or hypertension-may have prognostic implications. Fourth, novel cardiovascular risk factors may add further information about cardiovascular disease risk in older adults. Promising potential candidates identified in the Cardiovascular Health Study include markers of hemostatic activation, fibrinogen, factor VIII coagulant activity, C-reactive protein, and exposure to herpes simplex virus-1 and possibly chlamydia. Future Cardiovascular Health Study investigations will help to clarify which combination of traditional and newer risk factors provides the best estimate of cardiovascular risk for older adults.

%B Am J Geriatr Cardiol %V 13 %P 69-80 %8 2004 Mar-Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/15010653?dopt=Abstract %R 10.1111/j.1076-7460.2004.02123.x %0 Journal Article %J Stroke %D 2005 %T Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. %A Mukamal, Kenneth J %A Chung, Hyoju %A Jenny, Nancy S %A Kuller, Lewis H %A Longstreth, W T %A Mittleman, Murray A %A Burke, Gregory L %A Cushman, Mary %A Beauchamp, Norman J %A Siscovick, David S %K Aged %K Alcohol Drinking %K Apolipoproteins E %K Brain Infarction %K Brain Ischemia %K Cohort Studies %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Genotype %K Humans %K Hypertension %K Inflammation %K Ischemia %K Lipids %K Male %K Middle Aged %K Multivariate Analysis %K Myocardial Infarction %K Prospective Studies %K Risk %K Risk Factors %K Stroke %K Substance-Related Disorders %K Thrombosis %K Time Factors %K Vascular Diseases %X

BACKGROUND AND PURPOSE: The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype.

METHODS: We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly.

RESULTS: During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95% CI, 0.63 to 1.13), 0.75 (95% CI, 0.53 to 1.06), 0.82 (95% CI, 0.51 to 1.30), and 1.03 (95% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and > or =14 drinks per week (P quadratic trend 0.06). ApoE genotype appeared to modify the alcohol-ischemic stroke relationship (P interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors.

CONCLUSIONS: In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.

%B Stroke %V 36 %P 1830-4 %8 2005 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16081863?dopt=Abstract %R 10.1161/01.STR.0000177587.76846.89 %0 Journal Article %J Am J Hypertens %D 2005 %T beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study. %A Hindorff, Lucia A %A Heckbert, Susan R %A Psaty, Bruce M %A Lumley, Thomas %A Siscovick, David S %A Herrington, David M %A Edwards, Karen L %A Tracy, Russell P %K African Americans %K Antihypertensive Agents %K Arteriosclerosis %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Genotype %K Homozygote %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Polymorphism, Genetic %K Receptors, Adrenergic, beta-2 %K Risk Factors %X

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.

%B Am J Hypertens %V 18 %P 392-7 %8 2005 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/15797659?dopt=Abstract %R 10.1016/j.amjhyper.2004.10.014 %0 Journal Article %J Ophthalmology %D 2005 %T Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities & Cardiovascular Health studies. %A Wong, Tien Yin %A Larsen, Emily K Marino %A Klein, Ronald %A Mitchell, Paul %A Couper, David J %A Klein, Barbara E K %A Hubbard, Larry D %A Siscovick, David S %A Sharrett, A Richey %K Aged %K Aged, 80 and over %K Arterioles %K Blood Pressure %K Cardiovascular Diseases %K Carotid Stenosis %K Coronary Artery Disease %K Cross-Sectional Studies %K Embolism %K Female %K Fibrinogen %K Humans %K Hypertension %K Lipoprotein(a) %K Male %K Meta-Analysis as Topic %K Middle Aged %K Retinal Artery %K Retinal Vein Occlusion %K Risk Factors %X

OBJECTIVE: To examine the associations of retinal vein occlusion and arteriolar emboli with cardiovascular disease.

DESIGN: Population-based cross-sectional study.

PARTICIPANTS: Pooled from the Atherosclerosis Risk in Communities Study (n = 12,642; mean age, 60 years) and the Cardiovascular Health Study (n = 2824; mean age, 79 years).

METHODS: Retinal vein occlusion and arteriolar emboli were identified from a single nonmydriatic retinal photograph using a standardized protocol. Photographs were also graded for arteriovenous nicking and focal arteriolar narrowing. All participants had a comprehensive systemic evaluation, including standardized carotid ultrasonography.

MAIN OUTCOME MEASURES: Retinal vein occlusion and arteriolar emboli.

RESULTS: Prevalences of retinal vein occlusion and arteriolar emboli were 0.3% (n = 39 cases) and 0.2% (n = 34 cases), respectively. After adjusting for age, retinal vein occlusion was associated with hypertension (odds ratio [OR], 2.96; 95% confidence interval [CI], 1.43-6.14), systolic blood pressure (BP) (OR, 4.12; 95% CI, 1.40-12.16; highest quartile vs. lowest), diastolic BP (OR, 2.64; 95% CI, 1.07-6.46; highest quartile vs. lowest), carotid artery plaque (OR, 5.62; 95% CI, 2.60-12.16), body mass index (OR, 3.88; 95% CI, 1.23-12.18; highest quartile vs. lowest), plasma fibrinogen (OR, 3.29; 95% CI, 1.08-10.02; highest quartile vs. lowest), arteriovenous nicking (OR, 4.09; 95% CI, 2.00-8.36), and focal arteriolar narrowing (OR, 5.17; 95% CI, 2.59-10.29). After adjusting for age, retinal arteriolar emboli were associated with hypertension (OR, 3.14; 95% CI, 1.44-6.84), systolic BP (OR, 3.46; 95% CI, 1.13-10.65; highest quartile vs. lowest), prevalent coronary heart disease (OR, 2.33; 95% CI, 1.01-5.42), carotid artery plaque (OR, 4.62; 95% CI, 1.85-11.57), plasma lipoprotein (a) (OR, 3.69; 95% CI, 1.20-11.41; highest quartile vs. lowest), plasma fibrinogen (OR, 3.09; 95% CI, 0.98-9.76; highest quartile vs. lowest), and current cigarette smoking (OR, 3.08; 95% CI, 1.47-6.47). Approximately a quarter of participants with retinal vein occlusion and arteriolar emboli had evidence of carotid artery plaque as defined from ultrasound.

CONCLUSIONS: Retinal vein occlusion and retinal arteriolar emboli are associated with carotid artery disease, hypertension, and other cardiovascular risk factors.

%B Ophthalmology %V 112 %P 540-7 %8 2005 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15808241?dopt=Abstract %R 10.1016/j.ophtha.2004.10.039 %0 Journal Article %J Arch Intern Med %D 2005 %T Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study. %A O'Hare, Ann M %A Newman, Anne B %A Katz, Ronit %A Fried, Linda F %A Stehman-Breen, Catherine O %A Seliger, Stephen L %A Siscovick, David S %A Shlipak, Michael G %K Aged %K Cohort Studies %K Cystatin C %K Cystatins %K Female %K Health Surveys %K Humans %K Longitudinal Studies %K Male %K Peripheral Vascular Diseases %K Predictive Value of Tests %K Risk Factors %K ROC Curve %K United States %X

BACKGROUND: The association of cystatin C, a novel marker of renal function, with risk for developing complications related to peripheral arterial disease (PAD) has not been examined.

METHODS: We evaluated the hypothesis that a high cystatin C concentration is independently associated with future PAD events among 4025 participants in the Cardiovascular Health Study who underwent serum cystatin C measurement at the 1992-1993 visit and who did not have PAD at baseline. The association of cystatin C quintiles with time to first lower-extremity PAD procedure (bypass surgery, angioplasty, or amputation) was evaluated using multivariable proportional hazards models. Secondary analyses were conducted using quintiles of serum creatinine level and estimated glomerular filtration rate (eGFR).

RESULTS: The annualized risk of undergoing a procedure for PAD was 0.43% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95% confidence interval, 1.2-5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses.

CONCLUSION: Elevated concentrations of cystatin C were independently predictive of incident PAD events among community-dwelling elderly patients.

%B Arch Intern Med %V 165 %P 2666-70 %8 2005 Dec 12-26 %G eng %N 22 %1 https://www.ncbi.nlm.nih.gov/pubmed/16344426?dopt=Abstract %R 10.1001/archinte.165.22.2666 %0 Journal Article %J J Am Soc Nephrol %D 2005 %T Cystatin C and subclinical brain infarction. %A Seliger, Stephen L %A Longstreth, W T %A Katz, Ronit %A Manolio, Teri %A Fried, Linda F %A Shlipak, Michael %A Stehman-Breen, Catherine O %A Newman, Anne %A Sarnak, Mark %A Gillen, Daniel L %A Bleyer, Anthony %A Siscovick, David S %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Brain Infarction %K Confidence Intervals %K Creatinine %K Cross-Sectional Studies %K Cystatin C %K Cystatins %K Disease Progression %K Female %K Geriatric Assessment %K Humans %K Incidence %K Ischemic Attack, Transient %K Magnetic Resonance Imaging %K Male %K Odds Ratio %K Predictive Value of Tests %K Prognosis %K Risk Assessment %K Sensitivity and Specificity %K Severity of Illness Index %K Sex Factors %K Survival Analysis %X

Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a renal function marker. A cross-sectional study was performed among older adults in the Cardiovascular Health Study to examine associations between SBI and two serum markers of renal function: Serum creatinine (SCr) and cystatin C (CysC). Patients had cranial magnetic resonance imaging and renal markers measured in 1992 to 1993. Logistic regression was used to estimate the associations between renal function (estimated by 1/SCr and 1/CysC) and SBI, controlling for potential confounding factors. SBI were present in 789 (28.7%) of 2784 participants. A linear association with SBI was observed for 1/CysC (per 1-SD decrement; odds ratio [OR] 1.20; 95% confidence interval [CI] 1.09 to 1.32; P < 0.001) but not for 1/SCr (OR 1.08; 95% CI 0.98 to 1.19; P = 0.14), for which a quadratic U-shaped association was suggested (P = 0.004). In a model with both markers, 1/CysC was linearly associated with SBI (OR 1.26; P < 0.001), whereas 1/SCr was not (OR 1.06; P = 0.3). The prevalence of SBI was directly associated with quintile of CysC, whereas the association between SCr and SBI was U-shaped, with greater prevalence at high and low levels. Compared with creatinine, CysC, a novel marker of renal function, has a stronger and more direct association with SBI in the elderly.

%B J Am Soc Nephrol %V 16 %P 3721-7 %8 2005 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/16236809?dopt=Abstract %R 10.1681/ASN.2005010006 %0 Journal Article %J N Engl J Med %D 2005 %T Cystatin C and the risk of death and cardiovascular events among elderly persons. %A Shlipak, Michael G %A Sarnak, Mark J %A Katz, Ronit %A Fried, Linda F %A Seliger, Stephen L %A Newman, Anne B %A Siscovick, David S %A Stehman-Breen, Catherine %K Aged %K Biomarkers %K Cardiovascular Diseases %K Cerebrospinal Fluid Proteins %K Creatinine %K Cystatin C %K Cystatins %K Female %K Follow-Up Studies %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Diseases %K Male %K Mortality %K Multivariate Analysis %K Prognosis %K Risk %X

BACKGROUND: Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass. We compared creatinine and cystatin C levels as predictors of mortality from cardiovascular causes and from all causes in the Cardiovascular Health Study, a cohort study of elderly persons living in the community.

METHODS: Creatinine and cystatin C were measured in serum samples collected from 4637 participants at the study visit in 1992 or 1993; follow-up continued until June 30, 2001. For each measure, the study population was divided into quintiles, with the fifth quintile subdivided into thirds (designated 5a, 5b, and 5c).

RESULTS: Higher cystatin C levels were directly associated, in a dose-response manner, with a higher risk of death from all causes. As compared with the first quintile, the hazard ratios (and 95 percent confidence intervals) for death were as follows: second quintile, 1.08 (0.86 to 1.35); third quintile, 1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66); quintile 5a, 1.77 (1.34 to 2.26); 5b, 2.18 (1.72 to 2.78); and 5c, 2.58 (2.03 to 3.27). In contrast, the association of creatinine categories with mortality from all causes appeared to be J-shaped. As compared with the two lowest quintiles combined (cystatin C level, < or =0.99 mg per liter), the highest quintile of cystatin C (> or =1.29 mg per liter) was associated with a significantly elevated risk of death from cardiovascular causes (hazard ratio, 2.27 [1.73 to 2.97]), myocardial infarction (hazard ratio, 1.48 [1.08 to 2.02]), and stroke (hazard ratio, 1.47 [ 1.09 to 1.96]) after multivariate adjustment. The fifth quintile of creatinine, as compared with the first quintile, was not independently associated with any of these three outcomes.

CONCLUSIONS: Cystatin C, a serum measure of renal function, is a stronger predictor of the risk of death and cardiovascular events in elderly persons than is creatinine.

%B N Engl J Med %V 352 %P 2049-60 %8 2005 May 19 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/15901858?dopt=Abstract %R 10.1056/NEJMoa043161 %0 Journal Article %J Arch Intern Med %D 2005 %T Fish consumption and stroke risk in elderly individuals: the cardiovascular health study. %A Mozaffarian, Dariush %A Longstreth, W T %A Lemaitre, Rozenn N %A Manolio, Teri A %A Kuller, Lewis H %A Burke, Gregory L %A Siscovick, David S %K Age Distribution %K Aged %K Aged, 80 and over %K Animals %K Cohort Studies %K Confidence Intervals %K Diet %K Fatty Acids, Omega-3 %K Female %K Fish Oils %K Fishes %K Humans %K Incidence %K Male %K Multivariate Analysis %K Probability %K Proportional Hazards Models %K Risk Assessment %K Seafood %K Sensitivity and Specificity %K Sex Distribution %K Stroke %K Surveys and Questionnaires %K Survival Rate %K United States %X

BACKGROUND: Associations between fish consumption and stroke risk have been inconsistent, possibly because of the differences in types of fish meals consumed. Additionally, such relationships have not been specifically evaluated in the elderly, in whom disease burden may be high and diet less influential.

METHODS: Among 4775 adults 65 years or older (range, 65-98 years) and free of known cerebrovascular disease at baseline in 1989-1990, usual dietary intake was assessed using a food frequency questionnaire. In a subset, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches (fish burgers), correlated with plasma phospholipid long-chain n-3 fatty acid levels. Incident strokes were prospectively ascertained.

RESULTS: During 12 years of follow-up, participants experienced 626 incident strokes, including 529 ischemic strokes. In multivariate analyses, tuna/other fish consumption was inversely associated with total stroke (P = .04) and ischemic stroke (P = .02), with 27% lower risk of ischemic stroke with an intake of 1 to 4 times per week (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.98) and 30% lower risk with intake of 5 or more times per week (HR, 0.70; 95% CI, 0.50-0.99) compared with an intake of less than once per month. In contrast, fried fish/fish sandwich consumption was positively associated with total stroke (P = .006) and ischemic stroke (P = .003), with a 44% higher risk of ischemic stroke with consumption of more than once per week (HR, 1.44; 95% CI, 1.12-1.85) compared with consumption of less than once per month. Fish consumption was not associated with hemorrhagic stroke.

CONCLUSIONS: Among elderly individuals, consumption of tuna or other broiled or baked fish is associated with lower risk of ischemic stroke, while intake of fried fish or fish sandwiches is associated with higher risk. These results suggest that fish consumption may influence stroke risk late in life; potential mechanisms and alternate explanations warrant further study.

%B Arch Intern Med %V 165 %P 200-6 %8 2005 Jan 24 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/15668367?dopt=Abstract %R 10.1001/archinte.165.2.200 %0 Journal Article %J J Am Coll Cardiol %D 2005 %T Fish intake and risk of incident heart failure. %A Mozaffarian, Dariush %A Bryson, Chris L %A Lemaitre, Rozenn N %A Burke, Gregory L %A Siscovick, David S %K Aged %K Animals %K Cohort Studies %K Cooking %K Diet %K Diet Surveys %K Disease-Free Survival %K Female %K Fishes %K Heart Failure %K Humans %K Incidence %K Male %K Risk Factors %K United States %X

OBJECTIVES: Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF).

BACKGROUND: The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown.

METHODS: Among 4,738 adults age > or =65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated.

RESULTS: During 12 years' follow-up, 955 participants developed CHF. In multivariate-adjusted analyses, tuna/other fish consumption was inversely associated with incident CHF, with 20% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.64 to 0.99), 31% lower risk with intake 3 to 4 times/week (HR = 0.69, 95% CI = 0.52 to 0.91), and 32% lower risk with intake > or =5 times/week (HR = 0.68, 95% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009). In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37% lower risk in the highest quintile of intake (HR = 0.73, 95% CI = 0.57 to 0.94) compared with the lowest.

CONCLUSIONS: Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.

%B J Am Coll Cardiol %V 45 %P 2015-21 %8 2005 Jun 21 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15963403?dopt=Abstract %R 10.1016/j.jacc.2005.03.038 %0 Journal Article %J J Am Geriatr Soc %D 2005 %T Hospitalization for pneumonia in the Cardiovascular Health Study: incidence, mortality, and influence on longer-term survival. %A O'Meara, Ellen S %A White, Mark %A Siscovick, David S %A Lyles, Mary F %A Kuller, Lewis H %K Aged %K Aged, 80 and over %K Cognition %K Comorbidity %K Diabetes Complications %K Female %K Hospitalization %K Humans %K Male %K Mortality %K Pneumonia %K Prospective Studies %K Respiratory Physiological Phenomena %K Risk Factors %K Smoking %X

OBJECTIVES: To estimate the rate of hospitalization for pneumonia in community-dwelling older adults and to assess its risk factors and contribution to mortality.

DESIGN: Prospective observational study.

SETTING: The Cardiovascular Health Study (CHS) in four U.S. communities.

PARTICIPANTS: Five thousand eight hundred eighty-eight men and women aged 65 and older who were followed for a median 10.7 years.

MEASUREMENTS: Participants were interviewed about medical history and demographics; evaluated for lung, physical, and cognitive function; and followed for hospitalizations, cardiovascular disease, and death.

RESULTS: Nearly 10% of the cohort was hospitalized for pneumonia, for a rate of 11.1 per 1,000 person-years (95% confidence interval (CI)=10.2-12.0). Risk factors included older age, male sex, current and past smoking, poor physical and lung function, and history of cardiovascular disease and chronic obstructive pulmonary disease. Ten percent of participants died during their incident pneumonia hospitalization, and death rates were high in those who survived to discharge. Compared with participants who had not been hospitalized for pneumonia, the relative risk of total mortality was 4.9 (95% CI=4.1-6.0) during the first year after hospitalization and 2.6 (95% CI=2.2-3.1) thereafter, adjusted for age, sex, and race. The respective relative risks were 3.9 (95% CI=3.1-4.8) and 2.0 (95% CI=1.6-2.4) after further adjustment for baseline history of cardiovascular disease; diabetes mellitus; smoking; and measures of lung, physical, and cognitive function.

CONCLUSION: In older people, hospitalization for pneumonia is common and is associated with an elevated risk of death, as shown in this population-based, prospective cohort.

%B J Am Geriatr Soc %V 53 %P 1108-16 %8 2005 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/16108926?dopt=Abstract %R 10.1111/j.1532-5415.2005.53352.x %0 Journal Article %J J Am Geriatr Soc %D 2006 %T Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study. %A Mukamal, Kenneth J %A Chung, Hyoju %A Jenny, Nancy S %A Kuller, Lewis H %A Longstreth, W T %A Mittleman, Murray A %A Burke, Gregory L %A Cushman, Mary %A Psaty, Bruce M %A Siscovick, David S %K Aged %K Alcohol Drinking %K Apolipoproteins E %K Beer %K Cohort Studies %K Coronary Disease %K Female %K Genotype %K Health Behavior %K Humans %K Incidence %K Male %K Residence Characteristics %K Risk Assessment %K Socioeconomic Factors %K United States %K Wine %X

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome.

DESIGN: Prospective cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline.

MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly.

RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele.

CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.

%B J Am Geriatr Soc %V 54 %P 30-7 %8 2006 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/16420195?dopt=Abstract %R 10.1111/j.1532-5415.2005.00561.x %0 Journal Article %J Health Care Financ Rev %D 2006 %T Alcohol consumption in older adults and Medicare costs. %A Mukamal, Kenneth J %A Lumley, Thomas %A Luepker, Russell V %A Lapin, Pauline %A Mittleman, Murray A %A McBean, A Marshall %A Crum, Rosa M %A Siscovick, David S %K Aged %K Alcohol Drinking %K Cardiovascular Diseases %K Female %K Health Expenditures %K Hospitalization %K Humans %K Longitudinal Studies %K Male %K Medicare %K United States %X

We determined the relationship of alcohol consumption and Medicare costs among 4,392 participants in the Cardiovascular Health Study (CHS), a longitudinal, population-based cohort study of adults age 65 or over in four U.S. communities. We assessed 5-year Parts A and B costs and self-reported intake of beer, wine, and liquor at baseline. Among both sexes, total costs were approximately $2,000 lower among consumers of > 1-6 drinks per week than abstainers. The lower costs associated with moderate drinking were most apparent among participants with cardiovascular disease (CVD) and for hospitalization costs for CVD among healthy participants. Former drinkers had the highest costs.

%B Health Care Financ Rev %V 27 %P 49-61 %8 2006 Spring %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/17290648?dopt=Abstract %0 Journal Article %J J Am Coll Cardiol %D 2006 %T The association of alcohol consumption and incident heart failure: the Cardiovascular Health Study. %A Bryson, Chris L %A Mukamal, Kenneth J %A Mittleman, Murray A %A Fried, Linda P %A Hirsch, Calvin H %A Kitzman, Dalane W %A Siscovick, David S %K Aged %K Alcohol Drinking %K Chi-Square Distribution %K Comorbidity %K Female %K Heart Failure %K Humans %K Life Style %K Male %K Multicenter Studies as Topic %K Myocardial Infarction %K Proportional Hazards Models %K Risk Factors %K Smoking %X

OBJECTIVES: We investigated the association between alcohol consumption and incident congestive heart failure (CHF) both overall and after adjusting for incident myocardial infarction (MI).

BACKGROUND: Moderate alcohol consumption has been associated with lower risk of CHF and MI.

METHODS: The Cardiovascular Health study, a prospective cohort study of cardiovascular disease risk factors and outcomes, followed 5,888 subjects > or =65 years old for 7 to 10 years. Cox models were used to estimate the adjusted risk of CHF by reported alcohol consumption.

RESULTS: There were 5,595 subjects at baseline at risk for incident CHF with alcohol data and 1,056 events during follow-up. Compared with abstainers, the adjusted risk of CHF was lower among subjects who reported consuming 1 to 6 drinks per week (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67 to 1.00, p = 0.05) and 7 to 13 drinks per week (HR 0.66, 95% CI 0.47 to 0.91, p = 0.01). Time-dependent adjustment for incident MI altered only slightly the association between moderate alcohol consumption and CHF (for 1 to 6 drinks per week, HR 0.84, 95% CI 0.65 to 1.04; for 7 to 13 drinks per week, HR 0.69, 95% CI 0.49 to 0.99). Baseline former drinkers had a higher risk of CHF than abstainers (HR 1.51, p < 0.01), but those who quit during the study did not have a higher risk (HR 0.83, 95% CI 0.66 to 1.03).

CONCLUSIONS: Moderate alcohol use is associated with a lower risk of incident CHF among older adults, even after accounting for incident MI and other factors.

%B J Am Coll Cardiol %V 48 %P 305-11 %8 2006 Jul 18 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16843180?dopt=Abstract %R 10.1016/j.jacc.2006.02.066 %0 Journal Article %J Circulation %D 2006 %T Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. %A Sotoodehnia, Nona %A Siscovick, David S %A Vatta, Matteo %A Psaty, Bruce M %A Tracy, Russell P %A Towbin, Jeffrey A %A Lemaitre, Rozenn N %A Rea, Thomas D %A Durda, J Peter %A Chang, Joel M %A Lumley, Thomas S %A Kuller, Lewis H %A Burke, Gregory L %A Heckbert, Susan R %K African Continental Ancestry Group %K Aged %K Case-Control Studies %K Death, Sudden, Cardiac %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Glutamine %K Haplotypes %K Homozygote %K Humans %K Male %K Polymorphism, Single Nucleotide %K Receptors, Adrenergic, beta-2 %K Reproducibility of Results %X

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.

%B Circulation %V 113 %P 1842-8 %8 2006 Apr 18 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/16618831?dopt=Abstract %R 10.1161/CIRCULATIONAHA.105.582833 %0 Journal Article %J Ann Intern Med %D 2006 %T Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. %A Shlipak, Michael G %A Katz, Ronit %A Sarnak, Mark J %A Fried, Linda F %A Newman, Anne B %A Stehman-Breen, Catherine %A Seliger, Stephen L %A Kestenbaum, Brian %A Psaty, Bruce %A Tracy, Russell P %A Siscovick, David S %K Aged %K Biomarkers %K Cardiovascular Diseases %K Creatinine %K Cystatin C %K Cystatins %K Glomerular Filtration Rate %K Humans %K Kidney %K Longitudinal Studies %K Prognosis %K Proportional Hazards Models %K Renal Insufficiency, Chronic %K Risk Factors %X

BACKGROUND: Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR] > or =60 mL/min per 1.73 m2).

OBJECTIVE: To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.

DESIGN: Cohort study.

SETTING: The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.

PARTICIPANTS: 4663 elderly persons.

MEASUREMENTS: Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).

RESULTS: At baseline, 78% of participants did not have chronic kidney disease (estimated GFR > or =60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 micromol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (> or =1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.

LIMITATIONS: Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.

CONCLUSIONS: Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a "preclinical" state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.

%B Ann Intern Med %V 145 %P 237-46 %8 2006 Aug 15 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/16908914?dopt=Abstract %R 10.7326/0003-4819-145-4-200608150-00003 %0 Journal Article %J J Am Coll Cardiol %D 2006 %T Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. %A Mozaffarian, Dariush %A Prineas, Ronald J %A Stein, Phyllis K %A Siscovick, David S %K Aged %K Animals %K Atrioventricular Node %K Cross-Sectional Studies %K Diet %K Electrocardiography %K Fatty Acids, Omega-3 %K Female %K Fishes %K Heart %K Heart Rate %K Humans %K Male %K Ventricular Function %X

OBJECTIVES: We evaluated the association between dietary fish intake and several cardiac electrocardiographic parameters in humans relevant to arrhythmic risk.

BACKGROUND: Fish consumption may reduce the incidence of sudden death and atrial fibrillation, possibly related to anti-arrhythmic effects.

METHODS: In a population-based study of 5,096 men and women, we evaluated cross-sectional associations between usual dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). Multivariate models were adjusted for age, gender, race, education, smoking, body mass index, diabetes, coronary heart disease, physical activity, and intakes of beef or pork, fried fish, fruits, vegetables, alcohol, and total calories.

RESULTS: Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (-3.2 beats/min, 95% confidence interval [CI] = 1.3 to 5.1; p trend <0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95% CI = 3.3 to 11.9), and 46% lower likelihood of prolonged QT (relative risk = 0.54, 95% CI = 0.33 to 0.88).

CONCLUSIONS: These findings in this large, population-based study suggest that dietary fish intake is associated with cardiac electrophysiology in humans, including heart rate, atrioventricular conduction, and ventricular repolarization, with potential implications for arrhythmic risk.

%B J Am Coll Cardiol %V 48 %P 478-84 %8 2006 Aug 01 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/16875972?dopt=Abstract %R 10.1016/j.jacc.2006.03.048 %0 Journal Article %J Am J Cardiol %D 2006 %T Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics. %A Mozaffarian, Dariush %A Gottdiener, John S %A Siscovick, David S %K Animals %K Blood Pressure %K Cardiac Output %K Confounding Factors, Epidemiologic %K Cooking %K Heart Rate %K Hemodynamics %K Humans %K Seafood %K Tuna %K Vascular Resistance %X

Fish intake is associated with improved cardiovascular health, including a lower risk of arrhythmic death, atrial fibrillation, and heart failure. However, the physiologic effects that may produce these cardiovascular benefits are not well-established. We investigated the cross-sectional associations between a usual dietary intake of fish during the previous year and cardiac structure, function, and hemodynamics as determined by physical examination and 2-dimensional, Doppler, and M-mode transthoracic echocardiography among 5,073 older adults enrolled in the Cardiovascular Health Study. On multivariate-adjusted analyses, consumption of tuna or other broiled or baked fish was associated with a lower heart rate (p < 0.001), lower systemic vascular resistance (p = 0.002), and greater stroke volume (p < 0.001). Tuna/other fish intake was also associated with a higher E/A ratio (p = 0.004), a measure of more normal diastolic function. In contrast, fried fish or fish sandwich (fish burger) intake was associated with left ventricular wall motion abnormalities (p = 0.02), a reduced ejection fraction (p < 0.001), lower cardiac output (p = 0.04), a trend toward a larger left ventricular diastolic dimension (p = 0.07), and higher systemic vascular resistance (p = 0.003). In conclusion, in this large population-based study, the intake of tuna or other broiled or baked fish was associated with improved cardiac hemodynamics, but fried fish intake was associated with structural abnormalities indicative of systolic dysfunction and potential coronary atherosclerosis. These findings suggest potential specific physiologic mechanisms that may, in part, account for the effects of fish intake on cardiovascular health.

%B Am J Cardiol %V 97 %P 216-22 %8 2006 Jan 15 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16442366?dopt=Abstract %R 10.1016/j.amjcard.2005.08.025 %0 Journal Article %J Circulation %D 2006 %T Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study. %A Lemaitre, Rozenn N %A King, Irena B %A Mozaffarian, Dariush %A Sotoodehnia, Nona %A Rea, Thomas D %A Kuller, Lewis H %A Tracy, Russel P %A Siscovick, David S %K Aged %K Aged, 80 and over %K Biomarkers %K Case-Control Studies %K Coronary Disease %K Death, Sudden, Cardiac %K Female %K Humans %K Male %K Myocardial Ischemia %K Phospholipids %K Trans Fatty Acids %K United States %X

BACKGROUND: Intake of trans fatty acids is associated with increased risk of coronary heart disease. Whether different classes of trans fatty acids show similar associations is unclear. We previously reported an association of sudden cardiac death with red cell membrane trans-18:2 but not trans-18:1 fatty acids. To extend these findings, we investigated the associations of plasma phospholipid trans fatty acids with fatal ischemic heart disease (IHD) and sudden cardiac death.

METHODS AND RESULTS: We conducted a case-control study nested in the Cardiovascular Health Study. We identified 214 cases of fatal IHD (fatal myocardial infarction and coronary heart disease death) between 1992 and 1998. We randomly selected 214 controls, matched to cases on demographics, prevalent cardiovascular disease, and timing of blood draw. Plasma phospholipid fatty acids were assessed in blood samples collected earlier. Higher levels of plasma phospholipid trans-18:2 fatty acids were associated with higher risk of fatal IHD (odds ratio [OR] for interquintile range 1.68, 95% confidence interval [CI] 1.21 to 2.33) after adjustment for risk factors and trans-18:1 levels. Trans-18:1 levels above the 20th percentile were associated with lower risk (OR 0.34, 95% CI 0.18 to 0.63). In analyses limited to cases of sudden cardiac death (n=95), higher levels of trans-18:2 fatty acids were associated with higher risk (OR 2.34, 95% CI 1.27 to 4.31) and higher trans-18:1 with lower risk (OR 0.18, 95% CI 0.06 to 0.54).

CONCLUSIONS: Higher levels of trans-18:2 and lower levels of trans-18:1 fatty acids are associated with higher risks of fatal IHD and sudden cardiac death. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 content.

%B Circulation %V 114 %P 209-15 %8 2006 Jul 18 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/16818809?dopt=Abstract %R 10.1161/CIRCULATIONAHA.106.620336 %0 Journal Article %J Arch Intern Med %D 2006 %T Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. %A Wong, Tien Yin %A Kamineni, Aruna %A Klein, Ronald %A Sharrett, A Richey %A Klein, Barbara E %A Siscovick, David S %A Cushman, Mary %A Duncan, Bruce B %K Aged %K Aged, 80 and over %K Algorithms %K Cardiovascular Diseases %K Cohort Studies %K Female %K Humans %K Image Processing, Computer-Assisted %K Incidence %K Male %K Photography %K Prospective Studies %K Retinal Diseases %K Retinal Vein %K Retinal Vessels %K Risk Factors %K Stroke %K United States %X

BACKGROUND: Small vessel disease may contribute to the risk of cardiovascular disease in older persons. We describe the relation of retinal vascular caliber to incident coronary heart disease (CHD) and stroke in elderly persons.

METHODS: Prospective population-based cohort study composed of 1992 men and women aged 69 to 97 years living in 4 US communities. Retinal arteriolar and venular calibers were measured from retinal photographs using a computer-assisted method. Incident CHD and stroke events were ascertained using standardized methods.

RESULTS: After 5 years of follow-up, there were 115 incident CHD events and 113 incident stroke events. Participants with larger retinal venular caliber had a higher incidence of CHD (11.7%; 95% confidence interval [CI], 8.7%-15.8%, vs 8.1%; 95% CI, 5.7%-11.6%), comparing largest with smallest venular caliber quartiles, and stroke (8.4%; 95% CI, 6.0-11.7, vs 5.8%; 95% CI, 3.9-8.4). At multivariable analysis, controlling for age, sex, race, arteriolar caliber, systolic and diastolic blood pressure, diabetes, glucose concentration, cigarette smoking, pack-years of smoking, and high-density-lipoprotein and low-density lipoprotein cholesterol levels, larger retinal venular caliber was associated with incident CHD (rate ratio, 3.0; 95% CI, 1.6-5.7, comparing largest with smallest venular caliber quartiles; P(trend) = .001) and incident stroke (rate ratio, 2.2; 95% CI, 1.1-4.3; P(trend) = .02). Additional adjustment for C-reactive protein and common and internal carotid artery intimal-media thickness had minimal effect on these associations. At multivariable analysis, smaller retinal arteriolar caliber was associated with incident CHD (rate ratio, 2.0; 95% CI, 1.1-3.7, comparing largest with smallest arteriolar caliber quartiles; P = .03) but not stroke (rate ratio,1.1; 95% CI, 0.5-2.2; P = .73).

CONCLUSION: Larger retinal venular caliber is independently associated with risk of cardiovascular disease in elderly persons.

%B Arch Intern Med %V 166 %P 2388-94 %8 2006 Nov 27 %G eng %N 21 %1 https://www.ncbi.nlm.nih.gov/pubmed/17130394?dopt=Abstract %R 10.1001/archinte.166.21.2388 %0 Journal Article %J J Clin Endocrinol Metab %D 2007 %T Alcohol consumption and lipoprotein subclasses in older adults. %A Mukamal, Kenneth J %A Mackey, Rachel H %A Kuller, Lewis H %A Tracy, Russell P %A Kronmal, Richard A %A Mittleman, Murray A %A Siscovick, David S %K Aged %K Alcohol Drinking %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K Cholesterol, VLDL %K Coronary Disease %K Cross-Sectional Studies %K Female %K Humans %K Magnetic Resonance Spectroscopy %K Male %K Prevalence %K Risk Factors %X

CONTEXT: Limited evidence suggests that alcohol intake may be associated with lipoprotein subclass distribution, which could mediate its relationship with coronary heart disease.

OBJECTIVES: The objective was to determine the relationship of alcohol intake with lipoprotein particle subclasses.

DESIGN, SETTING, AND PARTICIPANTS: The study included a cross-sectional analysis of 1850 participants of the Cardiovascular Health Study aged 65 yr and older and free of clinical cardiovascular disease.

MAIN OUTCOME MEASURE: Lipoprotein subclass distribution was measured with nuclear magnetic resonance spectroscopy, according to self-reported alcohol intake.

RESULTS: Alcohol intake was associated with total low-density lipoprotein (LDL) particles in a U-shaped manner. Consumers of one or more drinks per week had the highest number of large LDL particles, whereas consumers of 7-13 drinks per week had the lowest number of small LDL particles. Alcohol intake was strongly positively associated with large- and medium-sized high-density lipoprotein (HDL) particles but had an inverse relationship with concentrations of small HDL particles and small- and medium-sized very-low-density lipoprotein particles. Average particle sizes of all three lipoproteins were positively associated with alcohol intake. Associations were generally stronger among women than men but in similar directions. Beverage type did not consistently modify these findings.

CONCLUSIONS: Alcohol intake is associated with less total LDL particles, lower levels of small LDL, HDL, and very-low-density lipoprotein particles, and higher levels of large LDL and medium- and large-sized HDL particles in older adults free of prevalent clinical cardiovascular disease.

%B J Clin Endocrinol Metab %V 92 %P 2559-66 %8 2007 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/17440017?dopt=Abstract %R 10.1210/jc.2006-2422 %0 Journal Article %J Am Heart J %D 2007 %T Alcohol consumption and risk and prognosis of atrial fibrillation among older adults: the Cardiovascular Health Study. %A Mukamal, Kenneth J %A Psaty, Bruce M %A Rautaharju, Pentti M %A Furberg, Curt D %A Kuller, Lewis H %A Mittleman, Murray A %A Gottdiener, John S %A Siscovick, David S %K Aged %K Alcohol Drinking %K Atrial Fibrillation %K Female %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Prognosis %K Risk Factors %X

BACKGROUND: The relationship of alcohol consumption with risk of atrial fibrillation (AF) is inconsistent in previous studies, and its relationship with prognosis of AF is undetermined.

METHODS: As part of the Cardiovascular Health Study, a population-based cohort of adults 65 years and older from 4 US communities, 5609 participants reported their use of beer, wine, and spirits yearly. We identified cases of AF with routine study electrocardiograms and validated discharge diagnoses from hospitalizations.

RESULTS: A total of 1232 cases of AF were documented during a mean of 9.1 years of follow-up. Compared with long-term abstainers, the multivariable-adjusted hazard ratios were 1.25 (95% CI, 1.02-1.54) among former drinkers, 1.09 (95% CI, 0.94-1.28) among consumers of less than 1 drink per week, 1.00 (95% CI, 0.84-1.19) among consumers of 1 to 6 drinks per week, 1.06 (95% CI, 0.82-1.37) among consumers of 7 to 13 drinks per week, and 1.09 (95% CI, 0.88-1.37) among consumers of 14 or more drinks per week (P trend = 0.64). In analyses of mortality among participants with AF, the hazard ratios were 1.27 (95% CI, 1.06-1.52) among former drinkers, 0.94 (95% CI, 0.76-1.18) among consumers of less than 1 drink per week, 0.98 (95% CI, 0.78-1.23) among consumers of 1 to 6 drinks per week, 0.73 (95% CI, 0.51-1.03) among consumers of 7 to 13 drinks per week, and 0.81 (95% CI, 0.59-1.11) among consumers of 14 or more drinks per week (P trend = 0.12).

CONCLUSIONS: Current moderate alcohol consumption is not associated with risk of AF or with risk of death after diagnosis of AF, but former drinking identifies individuals at higher risk.

%B Am Heart J %V 153 %P 260-6 %8 2007 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17239687?dopt=Abstract %R 10.1016/j.ahj.2006.10.039 %0 Journal Article %J Obesity (Silver Spring) %D 2007 %T Alcohol consumption and type 2 diabetes among older adults: the Cardiovascular Health Study. %A Djoussé, Luc %A Biggs, Mary L %A Mukamal, Kenneth J %A Siscovick, David S %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Diabetes Mellitus, Type 2 %K Female %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Medicare %K Middle Aged %K Risk %K Smoking %K Temperance %K United States %X

OBJECTIVE: The objective was to examine the role of total and beverage-specific alcohol consumption on the incidence of type 2 diabetes mellitus (DM) among elderly men and women.

RESEARCH METHODS AND PROCEDURES: We studied prospectively 4655 participants of the Cardiovascular Health Study who were free of DM at baseline. Alcohol consumption was obtained at baseline and during follow-up examinations. DM was defined using fasting glucose and/or use of hypoglycemic medications. We used Cox proportional hazard models to estimate adjusted relative risks of diabetes across alcohol categories.

RESULTS: During a mean follow-up of 6.3 years, 234 incident cases of DM were documented. Compared with never drinkers, hazard ratios [95% confidence interval (CI)] for DM were 0.7 (0.3 to 1.4), 0.5 (0.3 to 0.9), 0.6 (0.4 to 1.1), and 0.8 (0.4 to 1.3) for former drinkers and current drinkers of <1, 1 to 6, and 7+ drinks per week, respectively, for men after adjustment for age, BMI, education, and smoking. Corresponding values for women were 1.2 (0.6 to 2.3), 0.7 (0.4 to 1.1), 0.6 (0.3 to 1.1), and 0.4 (0.2 to 1.0), respectively. A reduced risk of DM was observed with all types of beverage consumed. Similar findings were observed when we repeated the above analyses using simple or weighted cumulative alcohol update and covariates over time.

DISCUSSION: Light to moderate alcohol consumption was associated with a lower incidence of DM among elderly people, irrespective of the type of beverage consumed.

%B Obesity (Silver Spring) %V 15 %P 1758-65 %8 2007 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/17636094?dopt=Abstract %R 10.1038/oby.2007.209 %0 Journal Article %J Am J Clin Nutr %D 2007 %T Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults. %A Mukamal, Kenneth J %A Jenny, Nancy S %A Tracy, Russell P %A Siscovick, David S %K Aged %K Alcohol Drinking %K Apolipoprotein E4 %K Apolipoproteins E %K Blood Glucose %K C-Reactive Protein %K Cohort Studies %K Female %K Genotype %K Humans %K Interleukin-6 %K Male %K Promoter Regions, Genetic %K Serum Amyloid P-Component %X

BACKGROUND: Whether alcohol intake is associated with concentrations of interleukin-6 (IL-6) and serum amyloid P (SAP) is uncertain.

OBJECTIVE: We determined how alcohol intake and apolipoprotein E (apo E) and IL-6 promoter (IL-6 -174G-->C) polymorphisms interact for concentrations of IL-6 and SAP.

DESIGN: In the Cardiovascular Health Study, 2454 older adults reported their intake of beer, wine, and liquor and underwent measurements of circulating IL-6 and SAP.

RESULTS: Alcohol intake was not associated with IL-6 concentrations among apo E4-negative or IL-6C-positive participants but was positively associated among both apo E4-positive and IL-6C-negative participants (P for trend = 0.02 for both). The corresponding interactions on SAP were not significant for alcohol overall but were similar for liquor intake.

CONCLUSIONS: Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations. Genetic heterogeneity should be considered in understanding the cardiovascular effects of alcohol intake.

%B Am J Clin Nutr %V 86 %P 444-50 %8 2007 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17684217?dopt=Abstract %R 10.1093/ajcn/86.2.444 %0 Journal Article %J Arch Ophthalmol %D 2007 %T Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study. %A Tikellis, Gabriella %A Sun, Cong %A Gorin, Michael B %A Klein, Ronald %A Klein, Barbara E K %A Larsen, Emily K Marino %A Siscovick, David S %A Hubbard, Larry D %A Wong, Tien Y %K African Americans %K Aged %K Aged, 80 and over %K Alleles %K Apolipoprotein E2 %K Apolipoprotein E3 %K Apolipoprotein E4 %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Genotype %K Humans %K Macular Degeneration %K Male %K Odds Ratio %K Polymorphism, Genetic %K Risk Factors %X

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.

%B Arch Ophthalmol %V 125 %P 68-73 %8 2007 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17210854?dopt=Abstract %R 10.1001/archopht.125.1.68 %0 Journal Article %J Am J Geriatr Psychiatry %D 2007 %T Are microvascular abnormalities in the retina associated with depression symptoms? The Cardiovascular Health Study. %A Sun, Cong %A Tikellis, Gabriella %A Klein, Ronald %A Steffens, David C %A Larsen, Emily K Marino %A Siscovick, David S %A Klein, Barbara E K %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Body Mass Index %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Cross-Sectional Studies %K Depression %K Female %K Fluorescein Angiography %K Humans %K Male %K Microcirculation %K Personality Inventory %K Retinal Artery Occlusion %K Retinal Diseases %K Retinal Vein Occlusion %K Risk Factors %K Statistics as Topic %K United States %X

OBJECTIVE: Depression has been linked with vascular risk factors and stroke. The authors examined the relationship between retinal microvascular abnormalities and depression symptoms in an elderly population.

METHODS: The Cardiovascular Health Study is a population-based study conducted in four U.S. communities initiated in 1989-1990. A total of 2,420 persons aged 65 years and older were included in the current analyses. During the 1997-1998 examination, retinal photographs were performed and assessed for retinal microvascular abnormalities (retinopathy, focal arteriolar narrowing, arteriovenous nicking, generalized retinal arteriolar narrowing, and generalized retinal venular dilation) according to standardized methods. Depression symptoms were assessed by a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998 and was defined as a CES-D score of >9.

RESULTS: Participants with retinal microvascular abnormalities were not more likely to have depression symptoms, with adjusted odds ratio (OR) (95% confidence intervals) of 1.08 (0.71-1.65) for retinopathy, OR 1.09 (0.71-1.68) for focal arteriolar narrowing, OR 0.85 (0.52-1.40) for arteriovenous nicking, OR 0.97 (0.70-1.34) for generalized arteriolar narrowing, and OR 0.79 (0.56-1.12) for generalized venular dilation. Retinal microvascular abnormalities were not related to depression symptoms in multinomial logistic regression comparing the three top quartiles of the depression CES-D scores with the lowest quartile.

CONCLUSIONS: Our study did not find an association between retinal microvascular abnormalities and depression symptoms in older people.

%B Am J Geriatr Psychiatry %V 15 %P 335-43 %8 2007 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/17384316?dopt=Abstract %R 10.1097/01.JGP.0000247161.98311.0f %0 Journal Article %J Clin J Am Soc Nephrol %D 2007 %T Kidney function, electrocardiographic findings, and cardiovascular events among older adults. %A Kestenbaum, Bryan %A Rudser, Kyle D %A Shlipak, Michael G %A Fried, Linda F %A Newman, Anne B %A Katz, Ronit %A Sarnak, Mark J %A Seliger, Stephen %A Stehman-Breen, Catherine %A Prineas, Ronald %A Siscovick, David S %K Aged %K Aged, 80 and over %K Cardiac Output, Low %K Cardiovascular Diseases %K Chronic Disease %K Coronary Disease %K Electrocardiography %K Female %K Humans %K Kidney %K Kidney Diseases %K Male %K Risk Assessment %X

Chronic kidney disease (CKD) is associated with cardiovascular (CV) disease and mortality. It is not known whether cardiac rhythm disturbances are more prevalent among individuals with CKD or whether resting electrocardiogram findings predict future CV events in the CKD setting. Data were obtained from the Cardiovascular Health Study, a community-based study of adults aged >/=65 yr. After exclusions for prevalent heart disease, atrial fibrillation, implantable pacemaker, or antiarrhythmic medication use, 3238 participants were analyzed. CKD was defined by an estimated GFR <60 ml/min per 1.73 m(2). Outcomes were adjudicated incident heart failure (HF), incident coronary heart disease (CHD), and mortality. Participants with CKD had longer PR and corrected QT intervals compared with those without CKD; however, differences in electrocardiographic markers were explained by traditional CV risk factors and CV medication use. After adjustment for known risk factors, each 10-ms increase in the QRS interval was associated with a 15% greater risk for incident HF (95% confidence interval [CI] 1.04 to 1.27), a 13% greater risk for CHD (95% CI 1.04 to 1.24), and a 17% greater risk for mortality (95% CI 1.09, 1.25) among CKD participants. Each 5% increase in QTI was associated with a 42% (95% CI 1.23 to 1.65), 22% (95% CI 1.07 to 1.40), and 10% (95% CI 0.98 to 1.22) greater risk for HF, CHD, and mortality, respectively. Associations seemed stronger for participants with CKD; however, no significant interactions were detected. Resting electrocardiographic abnormalities are common in CKD and independently predict future clinical CV events in this setting.

%B Clin J Am Soc Nephrol %V 2 %P 501-8 %8 2007 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/17699457?dopt=Abstract %R 10.2215/CJN.04231206 %0 Journal Article %J Am J Kidney Dis %D 2007 %T Relationship of uric acid with progression of kidney disease. %A Chonchol, Michel %A Shlipak, Michael G %A Katz, Ronit %A Sarnak, Mark J %A Newman, Anne B %A Siscovick, David S %A Kestenbaum, Bryan %A Carney, Jan Kirk %A Fried, Linda F %K Aged %K Aged, 80 and over %K Cohort Studies %K Cross-Sectional Studies %K Disease Progression %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Diseases %K Male %K Prospective Studies %K Uric Acid %X

BACKGROUND: Uric acid levels are increased in patients with kidney dysfunction. We tested the hypothesis that uric acid may be associated with kidney disease progression.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 5,808 participants of the Cardiovascular Health Study.

PREDICTOR: Uric acid levels.

OUTCOMES & MEASUREMENTS: Kidney disease progression was defined as a decrease in estimated glomerular filtration rate (GFR) of 3 mL/min/1.73 m(2) per year or greater (>or=0.05 mL/s) and as incident chronic kidney disease (CKD). Measures of kidney function were estimated GFR using the Modification of Diet in Renal Disease Study equation.

RESULTS: Higher quintiles of uric acid levels were associated with greater prevalences of estimated GFR less than 60 mL/min/1.73 m(2) (<1.00 mL/s) of 7%, 14%, 12%, 25%, and 42% for quintiles 1 (6.90 mg/dL [>410 micromol/L]), respectively. In comparison, there was only a modest, but significant, association between quintiles of uric acid levels and progression of kidney function decrease, with adjusted odds ratios of 1.0, 0.88 (95% confidence interval [CI], 0.64 to 1.21), 1.23 (95% CI, 0.87 to 1.75), 1.47 (95% CI, 1.04 to 2.07), and 1.49 (95% CI, 1.00 to 2.22) for quintiles 1 through 5, respectively. No significant association was found between uric acid level and incident CKD (adjusted odds ratio, 1.00; 95% CI, 0.89 to 1.14).

LIMITATIONS: Measurements of albuminuria were not available.

CONCLUSIONS: Uric acid levels are associated strongly with prevalent CKD. In comparison, greater uric acid levels had a significant, but much weaker, association with progression of kidney disease.

%B Am J Kidney Dis %V 50 %P 239-47 %8 2007 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17660025?dopt=Abstract %R 10.1053/j.ajkd.2007.05.013 %0 Journal Article %J Stroke %D 2007 %T Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. %A Baker, Michelle L %A Marino Larsen, Emily K %A Kuller, Lewis H %A Klein, Ronald %A Klein, Barbara E K %A Siscovick, David S %A Bernick, Charles %A Manolio, Teri A %A Wong, Tien Yin %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognition %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Longitudinal Studies %K Male %K Microcirculation %K Neuropsychological Tests %K Retinal Vessels %K Risk Factors %X

BACKGROUND AND PURPOSE: Cerebral microvascular disease may be a risk factor for the development of dementia in elderly persons. We describe the association of retinal microvascular signs with cognitive function and dementia among older individuals.

METHODS: In the population-based Cardiovascular Health Study, 2211 persons aged 69 to 97 years at recruitment had retinal photography. Photographs were evaluated for retinopathy (eg, microaneurysms, retinal hemorrhages), focal arteriolar narrowing, arteriovenous nicking, and retinal arteriolar and venular caliber. Cognitive status was determined from the Digit-Symbol Substitution Test and Modified Mini-Mental State Examination. Participants were also further evaluated for the presence of dementia with detailed neuropsychological testing. Persons with a prior stroke or taking antipsychotic or antidepressant medications were excluded.

RESULTS: After adjusting for age, gender, race, field center, education level, internal carotid intima-media thickness, body mass index, hypertension, diabetes, and cigarette smoking status, persons with retinopathy had lower mean Digit-Symbol Substitution Test scores but not Modified Mini-Mental State Examination than those without retinopathy (39 versus 41, P=0.002). In hypertensive persons, retinopathy (multivariable-adjusted OR, 2.10; 95% CI, 1.04 to 4.24) and focal arteriolar narrowing (OR, 3.02; 95% CI, 1.51 to 6.02) were associated with dementia. These associations were not present in individuals without hypertension.

CONCLUSIONS: In older persons, our study shows a modest cross-sectional association between retinopathy signs with poorer cognitive function and, in persons with hypertension, with dementia. These data support a possible role of cerebral microvascular disease in the pathogenesis of impaired cognitive function and dementia in older hypertensive persons.

%B Stroke %V 38 %P 2041-7 %8 2007 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/17525385?dopt=Abstract %R 10.1161/STROKEAHA.107.483586 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2007 %T USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies. %A Reiner, Alexander P %A Carlson, Christopher S %A Jenny, Nancy S %A Durda, J Peter %A Siscovick, David S %A Nickerson, Deborah A %A Tracy, Russell P %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Blood Glucose %K C-Reactive Protein %K Calcium %K Cardiovascular Diseases %K Carotid Artery, Common %K Cohort Studies %K Coronary Artery Disease %K Coronary Vessels %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Humans %K Hyperlipidemia, Familial Combined %K Insulin %K Interleukin-6 %K Linkage Disequilibrium %K Lipids %K Male %K Odds Ratio %K Phenotype %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %K Upstream Stimulatory Factors %X

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.

%B Arterioscler Thromb Vasc Biol %V 27 %P 2736-42 %8 2007 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/17885212?dopt=Abstract %R 10.1161/ATVBAHA.107.154559 %0 Journal Article %J Am J Epidemiol %D 2008 %T Alcohol consumption and lower extremity arterial disease among older adults: the cardiovascular health study. %A Mukamal, Kenneth J %A Kennedy, Margaret %A Cushman, Mary %A Kuller, Lewis H %A Newman, Anne B %A Polak, Joseph %A Criqui, Michael H %A Siscovick, David S %K Aged %K Alcohol Drinking %K Female %K Follow-Up Studies %K Health Surveys %K Humans %K Intermittent Claudication %K Male %K Prevalence %K Prospective Studies %K Risk Factors %K Surveys and Questionnaires %K Time Factors %K United States %X

Few studies of the relation of alcohol intake to lower-extremity arterial disease (LEAD) have included clinical events and objective measurements repeated longitudinally. As part of the Cardiovascular Health Study, a study of older adults from four US communities, 5,635 participants reported their use of beer, wine, and spirits yearly. Incident LEAD was identified by hospitalization surveillance. Technicians measured ankle-brachial index 6 years apart in 2,298 participants. A total of 172 cases of LEAD were documented during a mean of 7.5 years of follow-up between 1989 and 1999. Compared with abstention, the multivariable-adjusted hazard ratios were 1.10 (95% confidence interval (CI): 0.71, 1.71) for <1 alcoholic drink per week, 0.56 (95% CI: 0.33, 0.95) for 1-13 drinks per week, and 1.02 (95% CI: 0.53, 1.97) for > or =14 drinks per week (p for quadratic trend = 0.04). These relations were consistent within strata of sex, age, and apolipoprotein E genotype, and neither lipids nor inflammatory markers appeared to be important intermediates. Change in ankle-brachial index showed a similar relation (p for quadratic trend = 0.01). Alcohol consumption of 1-13 drinks per week in older adults may be associated with lower risk of LEAD, but heavier drinking is not associated with lower risk.

%B Am J Epidemiol %V 167 %P 34-41 %8 2008 Jan 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17971339?dopt=Abstract %R 10.1093/aje/kwm274 %0 Journal Article %J Stroke %D 2008 %T Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. %A Fornage, Myriam %A Chiang, Y Aron %A O'Meara, Ellen S %A Psaty, Bruce M %A Reiner, Alexander P %A Siscovick, David S %A Tracy, Russell P %A Longstreth, W T %K African Continental Ancestry Group %K Aged %K Biomarkers %K Brain Infarction %K C-Reactive Protein %K Cohort Studies %K European Continental Ancestry Group %K Female %K Haplotypes %K Humans %K Inflammation %K Interleukin-6 %K Magnetic Resonance Imaging %K Male %K Polymorphism, Single Nucleotide %X

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.

%B Stroke %V 39 %P 1952-9 %8 2008 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/18436879?dopt=Abstract %R 10.1161/STROKEAHA.107.508135 %0 Journal Article %J J Card Fail %D 2008 %T Cystatin C concentration as a predictor of systolic and diastolic heart failure. %A Moran, Andrew %A Katz, Ronit %A Smith, Nicolas L %A Fried, Linda F %A Sarnak, Mark J %A Seliger, Stephen L %A Psaty, Bruce %A Siscovick, David S %A Gottdiener, John S %A Shlipak, Michael G %K Aged %K Aged, 80 and over %K Biomarkers %K Cohort Studies %K Confidence Intervals %K Cystatin C %K Cystatins %K Echocardiography %K Female %K Heart Failure, Diastolic %K Heart Failure, Systolic %K Humans %K Longitudinal Studies %K Male %K Predictive Value of Tests %K Probability %K Proportional Hazards Models %K Risk Assessment %K Sensitivity and Specificity %K Stroke Volume %K Survival Analysis %X

BACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study.

METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50%) or SHF (EF < 50%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]).

CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.

%B J Card Fail %V 14 %P 19-26 %8 2008 Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/18226769?dopt=Abstract %R 10.1016/j.cardfail.2007.09.002 %0 Journal Article %J Circulation %D 2008 %T Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. %A Mozaffarian, Dariush %A Stein, Phyllis K %A Prineas, Ronald J %A Siscovick, David S %K Aged %K Aged, 80 and over %K Animals %K Cardiovascular Diseases %K Cohort Studies %K Cross-Sectional Studies %K Electrocardiography %K Fatty Acids, Omega-3 %K Female %K Fishes %K Heart Rate %K Humans %K Male %K Risk Factors %K Seafood %K Tuna %K United States %X

BACKGROUND: Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk.

METHODS AND RESULTS: In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincaré ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1% (for difference in standard deviation of normal-to-normal intervals) to 5.9% and 8.4% (for differences in Poincaré ratio and short-term fractal scaling exponent) lower risk.

CONCLUSIONS: Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.

%B Circulation %V 117 %P 1130-7 %8 2008 Mar 04 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/18285566?dopt=Abstract %R 10.1161/CIRCULATIONAHA.107.732826 %0 Journal Article %J Arch Intern Med %D 2008 %T Metabolic syndrome and mortality in older adults: the Cardiovascular Health Study. %A Mozaffarian, Dariush %A Kamineni, Aruna %A Prineas, Ronald J %A Siscovick, David S %K Aged %K Aged, 80 and over %K Blood Glucose %K Fasting %K Female %K Follow-Up Studies %K Humans %K Hypertension %K Male %K Metabolic Syndrome %K Multivariate Analysis %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K United States %X

BACKGROUND: The utility of metabolic syndrome (MetS) for predicting mortality among older adults, the highest-risk population, is not well established. In addition, few studies have compared the predictive utility of MetS to that of its individual risk factors.

METHODS: We evaluated relationships of MetS (as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III (ATPIII)], International Diabetes Foundation [IDF], and World Health Organization [WHO]) and individual MetS criteria with mortality between 1989 and 2004 among 4258 US adults 65 years or older and free of prevalent cardiovascular disease (CVD) in the Cardiovascular Health Study, a multicenter, population-based, prospective cohort. Total, CVD, and non-CVD mortality were evaluated. Cox proportional hazards models were used to estimate the mortality hazard ratio (relative risk [RR]) predicted by MetS.

RESULTS: At baseline (mean age, 73 years), 31% of men and 38% of women had MetS (ATPIII). During 15 years of follow-up, 2116 deaths occurred. After multivariable adjustment, compared with persons without MetS, those with MetS had a 22% higher mortality (RR, 1.22; 95% confidence interval [CI], 1.11-1.34). Higher risk with MetS was confined to persons having elevated fasting glucose level (EFG) (defined as > or = 110 mg/dL [> or = 6.1 mmol/L] or treated diabetes mellitus) (RR, 1.41; 95% CI, 1.27-1.57) or hypertension (RR, 1.26; 95% CI, 1.15-1.39) as one of the criteria; persons having MetS without EFG (RR, 0.97; 95% CI, 0.85-1.11) or MetS without hypertension (RR, 0.92; 95% CI, 0.71-1.19) did not have higher risk. Evaluating MetS criteria individually, we found that only hypertension and EFG predicted higher mortality; persons having both hypertension and EFG had 82% higher mortality (RR, 1.82; 95% CI, 1.58-109). Substantially higher proportions of deaths were attributable to EFG and hypertension (population attributable risk fraction [PAR%], 22.2%) than to MetS (PAR%, 6.3%). Results were similar when we used WHO or IDF criteria, when we evaluated different cut points of each individual criterion, and when we evaluated CVD mortality.

CONCLUSION: These findings suggest limited utility of MetS for predicting total or CVD mortality in older adults compared with assessment of fasting glucose and blood pressure alone.

%B Arch Intern Med %V 168 %P 969-78 %8 2008 May 12 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/18474761?dopt=Abstract %R 10.1001/archinte.168.9.969 %0 Journal Article %J J Am Coll Cardiol %D 2009 %T Association of chronic kidney disease with the spectrum of ankle brachial index the CHS (Cardiovascular Health Study). %A Ix, Joachim H %A Katz, Ronit %A de Boer, Ian H %A Kestenbaum, Brian R %A Allison, Matthew A %A Siscovick, David S %A Newman, Anne B %A Sarnak, Mark J %A Shlipak, Michael G %A Criqui, Michael H %K Aged %K Aged, 80 and over %K Ankle Brachial Index %K C-Reactive Protein %K Cardiovascular Diseases %K Chronic Disease %K Cohort Studies %K Cross-Sectional Studies %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Diseases %K Lipids %K Male %K Risk Factors %X

OBJECTIVES: This study sought to determine the association of chronic kidney disease (CKD) with high ankle brachial index (ABI) measurement and to compare its strength with that of CKD with a low ABI.

BACKGROUND: CKD is an important risk factor for cardiovascular disease (CVD) events. A high ABI, a marker of lower extremity arterial stiffness, is associated with CVD events and mortality. The association between CKD and high ABI is unknown.

METHODS: The CHS (Cardiovascular Health Study) enrolled community-living people >65 years of age and measured kidney function and ABI. Glomerular filtration rate (GFR) was estimated using equations that incorporated either cystatin C or creatinine, and CKD was defined by estimated GFR <60 ml/min/1.73 m(2). The ABI was categorized as low (<0.90), low-normal (0.90 to 1.09), normal (1.10 to 1.40), and high (>1.40 or incompressible). Multinomial logistic regression was used to evaluate the associations of CKD with ABI categories.

RESULTS: Among 4,513 participants, 23% had CKD, 13% had a low ABI, and 3% had a high ABI. In models adjusted for age, sex, race, hypertension, diabetes, smoking, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and C-reactive protein, cystatin C-based CKD was associated with both low ABI (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.6 to 2.5; p <0.001) and high ABI (RR: 1.6; 95% CI: 1.0 to 2.3; p = 0.03). Results were similar when CKD was defined by creatinine.

CONCLUSIONS: CKD is associated with both the high and the low extremes of ABI in community-living older people. Future studies should evaluate whether arterial stiffness is an important mechanism leading to CVD in people with CKD.

%B J Am Coll Cardiol %V 54 %P 1176-84 %8 2009 Sep 22 %G eng %N 13 %1 http://www.ncbi.nlm.nih.gov/pubmed/19761940?dopt=Abstract %R 10.1016/j.jacc.2009.06.017 %0 Journal Article %J Nephrol Dial Transplant %D 2009 %T Association of renal function with cardiac calcifications in older adults: the cardiovascular health study. %A Asselbergs, Folkert W %A Mozaffarian, Dariush %A Katz, Ronit %A Kestenbaum, Bryan %A Fried, Linda F %A Gottdiener, John S %A Shlipak, Michael G %A Siscovick, David S %K Aged %K Aortic Valve %K Calcinosis %K Case-Control Studies %K Cohort Studies %K Creatinine %K Cystatin C %K Female %K Glomerular Filtration Rate %K Heart Valve Diseases %K Humans %K Kidney Diseases %K Male %K Mitral Valve %K Risk Factors %X

BACKGROUND: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.

METHODS: From the Cardiovascular Health Study, a community-based cohort of ambulatory adults >or= age 65, a total of 3929 individuals (mean +/- SD age 74 +/- 5 years, 60% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.

RESULTS: The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m(2) (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m(2) was significantly associated with MAC [odds ratio 1.54 (95% CI 1.16-2.06), P = 0.003] and not associated with AAC [1.30 (0.97-1.74), P = 0.085] and AVS [1.15 (0.86-1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05-1.21), P = 0.001] and not associated with AAC [1.07 (1.00-1.15), P = 0.054] and AVS [0.99 (0.93-1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m(2) and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m(2), increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).

CONCLUSIONS: In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m(2) and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m(2), increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.

%B Nephrol Dial Transplant %V 24 %P 834-40 %8 2009 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18840892?dopt=Abstract %R 10.1093/ndt/gfn544 %0 Journal Article %J Diabetes Care %D 2009 %T Cystatin C, albuminuria, and mortality among older adults with diabetes. %A de Boer, Ian H %A Katz, Ronit %A Cao, Jie J %A Fried, Linda F %A Kestenbaum, Bryan %A Mukamal, Ken %A Rifkin, Dena E %A Sarnak, Mark J %A Shlipak, Michael G %A Siscovick, David S %K Aged %K Aged, 80 and over %K Albuminuria %K Creatinine %K Cystatin C %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Function Tests %K Male %K Risk Factors %X

OBJECTIVE: Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population.

RESEARCH DESIGN AND METHODS: This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples.

RESULTS: Of 691 participants, 378 died over 10 years of follow-up. Cystatin C-estimated GFR <60 ml/min per 1.73 m(2), creatinine-based estimated GFR <60 ml/min per 1.73 m(2), and urine ACR > or =30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95% CI 1.37-2.18), 1.54 (1.21-1.97), and 1.73 (1.39-2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C-estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C-estimated GFR predicted mortality more strongly than creatinine-based estimated GFR.

CONCLUSIONS: Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.

%B Diabetes Care %V 32 %P 1833-8 %8 2009 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/19587367?dopt=Abstract %R 10.2337/dc09-0191 %0 Journal Article %J Circulation %D 2009 %T Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. %A Kao, W H Linda %A Arking, Dan E %A Post, Wendy %A Rea, Thomas D %A Sotoodehnia, Nona %A Prineas, Ronald J %A Bishe, Bryan %A Doan, Betty Q %A Boerwinkle, Eric %A Psaty, Bruce M %A Tomaselli, Gordon F %A Coresh, Josef %A Siscovick, David S %A Marbán, Eduardo %A Spooner, Peter M %A Burke, Gregory L %A Chakravarti, Aravinda %K Adaptor Proteins, Signal Transducing %K Aged %K Death, Sudden, Cardiac %K Electrocardiography %K European Continental Ancestry Group %K Genotype %K Humans %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

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.

%B Circulation %V 119 %P 940-51 %8 2009 Feb 24 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/19204306?dopt=Abstract %R 10.1161/CIRCULATIONAHA.108.791723 %0 Journal Article %J Am J Kidney Dis %D 2009 %T Obesity and change in estimated GFR among older adults. %A de Boer, Ian H %A Katz, Ronit %A Fried, Linda F %A Ix, Joachim H %A Luchsinger, Jose %A Sarnak, Mark J %A Shlipak, Michael G %A Siscovick, David S %A Kestenbaum, Bryan %K Aged %K Aging %K Body Composition %K Body Mass Index %K Chronic Disease %K Cohort Studies %K Creatinine %K Cystatin C %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Diseases %K Longitudinal Studies %K Male %K Obesity %K Risk Factors %X

BACKGROUND: The prevalence of chronic kidney disease is growing most rapidly among older adults; however, determinants of impaired kidney function in this population are not well understood. Obesity assessed in midlife has been associated with chronic kidney disease.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 4,295 participants in the community-based Cardiovascular Health Study, aged >or= 65 years.

PREDICTORS: Body mass index, waist circumference, and fat mass measured using bioelectrical impedance.

OUTCOME: Change in glomerular filtration rate (GFR) during 7 years of follow-up.

MEASUREMENTS: Longitudinal estimates of GFR calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation.

RESULTS: Estimated GFR decreased by an average of 0.4 +/- 3.6 mL/min/1.73 m(2)/y, and rapid GFR loss (>3 mL/min/1.73 m(2)/y) occurred in 693 participants (16%). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: ORs, 1.19 (95% CI, 1.09-1.30) per 5 kg/m(2), 1.25 (95% CI, 1.16-1.36) per 12 cm, and 1.14 (95% CI, 1.05-1.24) per 10 kg after adjustment for age, sex, race, and smoking. The magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73 m(2) at baseline (P for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein level. Obesity measurements were not associated with change in GFR estimated using serum cystatin C level.

LIMITATIONS: Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements.

CONCLUSION: Obesity may be a modifiable risk factor for the development and progression of kidney disease in older adults.

%B Am J Kidney Dis %V 54 %P 1043-51 %8 2009 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19782454?dopt=Abstract %R 10.1053/j.ajkd.2009.07.018 %0 Journal Article %J Am J Nephrol %D 2009 %T Rate of kidney function decline in older adults: a comparison using creatinine and cystatin C. %A Shlipak, Michael G %A Katz, Ronit %A Kestenbaum, Bryan %A Fried, Linda F %A Newman, Anne B %A Siscovick, David S %A Stevens, Lesley %A Sarnak, Mark J %K Age Factors %K Aged %K Creatinine %K Cystatin C %K Disease Progression %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Diseases %K Male %K Risk Factors %X

BACKGROUND/AIMS: The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C.

METHODS: In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 +/- 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m(2)).

RESULTS: Mean annual eGFR loss as estimated from creatinine was 0.4 +/- 3.6 ml/min/1.73 m(2), with 16% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 +/- 2.6, with 25% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10% (n = 263) using creatinine and 19% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16-1.65), 1.62 (1.31-1.99) and 2.96 (2.28-3.84) for participants aged 70-74, 75-79 and 80+ at baseline, compared with those aged 65-69.

CONCLUSION: In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.

%B Am J Nephrol %V 30 %P 171-8 %8 2009 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/19349699?dopt=Abstract %R 10.1159/000212381 %0 Journal Article %J Nephrol Dial Transplant %D 2010 %T Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. %A Rifkin, Dena E %A Katz, Ronit %A Chonchol, Michel %A Fried, Linda F %A Cao, Jie %A de Boer, Ian H %A Siscovick, David S %A Shlipak, Michael G %A Sarnak, Mark J %K Aged %K Albuminuria %K Cardiovascular Diseases %K Creatinine %K Cystatin C %K Female %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Male %K Myocardial Infarction %K Risk Factors %X

BACKGROUND: Kidney disease is a risk factor for mortality and cardiovascular disease in older adults, but the separate and combined effects of albuminuria and cystatin C, a novel marker of glomerular filtration, are not known.

METHODS: We examined associations of these markers with mortality and cardiovascular outcomes during a median follow-up of 8.3 years in 3291 older adults in the Cardiovascular Health Study. Kidney disease was assessed using urinary albumin/creatinine ratio (ACR), cystatin C and Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR). We defined subgroups based on presence of microalbuminuria (MA, ACR > 30 mg/g) and categories of normal kidney function (cystatin C < 1.0 mg/L and eGFR > 60 mL/min/1.73 m(2)); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m(2)); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m(2)). Cox proportional hazards models were used to examine associations between these six subgroups and all-cause or cardiovascular mortality, myocardial infarction and heart failure.

RESULTS: One thousand one hundred fifty (34.9%) had normal kidney function (12.2% with MA), 1518 (46.1%) had preclinical kidney disease (17.9% with MA) and 622 (18.9%) had CKD (47% with MA). After adjustment, the presence of either preclinical kidney disease or MA was associated with an over 50% increase in mortality risk; the presence of both was associated with a 2.4-fold mortality risk. Those with CKD and MA were at highest risk, with a nearly 4-fold mortality risk.

CONCLUSION: Elevated cystatin C and albuminuria are common, identify different subsets of the older population, and are independent, graded risk factors for cardiovascular disease and mortality.

%B Nephrol Dial Transplant %V 25 %P 1560-7 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20008829?dopt=Abstract %R 10.1093/ndt/gfp646 %0 Journal Article %J Nephrol Dial Transplant %D 2010 %T Alcohol consumption and kidney function decline in the elderly: alcohol and kidney disease. %A Menon, Vandana %A Katz, Ronit %A Mukamal, Kenneth %A Kestenbaum, Bryan %A de Boer, Ian H %A Siscovick, David S %A Sarnak, Mark J %A Shlipak, Michael G %K Aged %K Aging %K Alcohol Drinking %K Cohort Studies %K Cystatin C %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Diseases %K Male %K Prospective Studies %X

BACKGROUND: Alcohol consumption appears to be protective for cardiovascular disease; however, its relationship with kidney disease is unclear.

METHODS: This prospective cohort study included 4343 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged ≥65 from four US communities. We used previously defined categories based on weekly alcohol consumption: none, former, <1 drink, 1-6 drinks, 7-13 drinks and ≥14 drinks. Cystatin C was measured at baseline, year 3 and year 7; eligible subjects had at least two measures. Estimated GFR(cys) was calculated from cystatin C. The primary outcome was rapid kidney function as an annual estimated GFR (eGFR(cys)) loss >3 mL/min/1.73 m(2)/year.

RESULTS: Eight percent of the cohort reported former alcohol use and 52% reported current alcohol consumption. During a mean follow-up of 5.6 years, 1075 (25%) participants had rapid kidney function decline. In adjusted logistic regression models, there was no association between alcohol use and kidney function decline (odds ratio, 95% confidence interval: none = reference; former = 1.18, 0.89-1.56; <1 drink = 1.20, 0.99-1.47; 1-6 = 1.18, 0.95-1.45; 7-13 = 1.10, 0.80-1.53; >14 = 0.89, 0.61-1.13). Results were similar with kidney function decline as a continuous outcome.

CONCLUSIONS: Our results suggest that moderate alcohol consumption has neither adverse nor beneficial effects on kidney function. Although clinicians will need to consider the potential deleterious effects associated with alcohol consumption, there does not appear to be a basis for recommending that older adults discontinue or initiate light to moderate alcohol consumption to protect against kidney disease.

%B Nephrol Dial Transplant %V 25 %P 3301-7 %8 2010 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/20400446?dopt=Abstract %R 10.1093/ndt/gfq188 %0 Journal Article %J Nat Genet %D 2010 %T Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. %A Speliotes, Elizabeth K %A Willer, Cristen J %A Berndt, Sonja I %A Monda, Keri L %A Thorleifsson, Gudmar %A Jackson, Anne U %A Lango Allen, Hana %A Lindgren, Cecilia M %A Luan, Jian'an %A Mägi, Reedik %A Randall, Joshua C %A Vedantam, Sailaja %A Winkler, Thomas W %A Qi, Lu %A Workalemahu, Tsegaselassie %A Heid, Iris M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Weedon, Michael N %A Wheeler, Eleanor %A Wood, Andrew R %A Ferreira, Teresa %A Weyant, Robert J %A Segrè, Ayellet V %A Estrada, Karol %A Liang, Liming %A Nemesh, James %A Park, Ju-Hyun %A Gustafsson, Stefan %A Kilpeläinen, Tuomas O %A Yang, Jian %A Bouatia-Naji, Nabila %A Esko, Tõnu %A Feitosa, Mary F %A Kutalik, Zoltán %A Mangino, Massimo %A Raychaudhuri, Soumya %A Scherag, Andre %A Smith, Albert Vernon %A Welch, Ryan %A Zhao, Jing Hua %A Aben, Katja K %A Absher, Devin M %A Amin, Najaf %A Dixon, Anna L %A Fisher, Eva %A Glazer, Nicole L %A Goddard, Michael E %A Heard-Costa, Nancy L %A Hoesel, Volker %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Ketkar, Shamika %A Lamina, Claudia %A Li, Shengxu %A Moffatt, Miriam F %A Myers, Richard H %A Narisu, Narisu %A Perry, John R B %A Peters, Marjolein J %A Preuss, Michael %A Ripatti, Samuli %A Rivadeneira, Fernando %A Sandholt, Camilla %A Scott, Laura J %A Timpson, Nicholas J %A Tyrer, Jonathan P %A van Wingerden, Sophie %A Watanabe, Richard M %A White, Charles C %A Wiklund, Fredrik %A Barlassina, Christina %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Lawrence, Robert W %A Pellikka, Niina %A Prokopenko, Inga %A Shi, Jianxin %A Thiering, Elisabeth %A Alavere, Helene %A Alibrandi, Maria T S %A Almgren, Peter %A Arnold, Alice M %A Aspelund, Thor %A Atwood, Larry D %A Balkau, Beverley %A Balmforth, Anthony J %A Bennett, Amanda J %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Bergmann, Sven %A Biebermann, Heike %A Blakemore, Alexandra I F %A Boes, Tanja %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Brown, Morris J %A Buchanan, Thomas A %A Busonero, Fabio %A Campbell, Harry %A Cappuccio, Francesco P %A Cavalcanti-Proença, Christine %A Chen, Yii-Der Ida %A Chen, Chih-Mei %A Chines, Peter S %A Clarke, Robert %A Coin, Lachlan %A Connell, John %A Day, Ian N M %A den Heijer, Martin %A Duan, Jubao %A Ebrahim, Shah %A Elliott, Paul %A Elosua, Roberto %A Eiriksdottir, Gudny %A Erdos, Michael R %A Eriksson, Johan G %A Facheris, Maurizio F %A Felix, Stephan B %A Fischer-Posovszky, Pamela %A Folsom, Aaron R %A Friedrich, Nele %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Gejman, Pablo V %A Geus, Eco J C %A Gieger, Christian %A Gjesing, Anette P %A Goel, Anuj %A Goyette, Philippe %A Grallert, Harald %A Grässler, Jürgen %A Greenawalt, Danielle M %A Groves, Christopher J %A Gudnason, Vilmundur %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hall, Alistair S %A Havulinna, Aki S %A Hayward, Caroline %A Heath, Andrew C %A Hengstenberg, Christian %A Hicks, Andrew A %A Hinney, Anke %A Hofman, Albert %A Homuth, Georg %A Hui, Jennie %A Igl, Wilmar %A Iribarren, Carlos %A Isomaa, Bo %A Jacobs, Kevin B %A Jarick, Ivonne %A Jewell, Elizabeth %A John, Ulrich %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Kaakinen, Marika %A Kajantie, Eero %A Kaplan, Lee M %A Kathiresan, Sekar %A Kettunen, Johannes %A Kinnunen, Leena %A Knowles, Joshua W %A Kolcic, Ivana %A König, Inke R %A Koskinen, Seppo %A Kovacs, Peter %A Kuusisto, Johanna %A Kraft, Peter %A Kvaløy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lanzani, Chiara %A Launer, Lenore J %A Lecoeur, Cécile %A Lehtimäki, Terho %A Lettre, Guillaume %A Liu, Jianjun %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Luben, Robert N %A Ludwig, Barbara %A Manunta, Paolo %A Marek, Diana %A Marre, Michel %A Martin, Nicholas G %A McArdle, Wendy L %A McCarthy, Anne %A McKnight, Barbara %A Meitinger, Thomas %A Melander, Olle %A Meyre, David %A Midthjell, Kristian %A Montgomery, Grant W %A Morken, Mario A %A Morris, Andrew P %A Mulic, Rosanda %A Ngwa, Julius S %A Nelis, Mari %A Neville, Matt J %A Nyholt, Dale R %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Ong, Ken K %A Oostra, Ben %A Paré, Guillaume %A Parker, Alex N %A Perola, Markus %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Polasek, Ozren %A Pouta, Anneli %A Rafelt, Suzanne %A Raitakari, Olli %A Rayner, Nigel W %A Ridderstråle, Martin %A Rief, Winfried %A Ruokonen, Aimo %A Robertson, Neil R %A Rzehak, Peter %A Salomaa, Veikko %A Sanders, Alan R %A Sandhu, Manjinder S %A Sanna, Serena %A Saramies, Jouko %A Savolainen, Markku J %A Scherag, Susann %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Silander, Kaisa %A Sinisalo, Juha %A Siscovick, David S %A Smit, Jan H %A Soranzo, Nicole %A Sovio, Ulla %A Stephens, Jonathan %A Surakka, Ida %A Swift, Amy J %A Tammesoo, Mari-Liis %A Tardif, Jean-Claude %A Teder-Laving, Maris %A Teslovich, Tanya M %A Thompson, John R %A Thomson, Brian %A Tönjes, Anke %A Tuomi, Tiinamaija %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Viikari, Jorma %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogel, Carla I G %A Voight, Benjamin F %A Waite, Lindsay L %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wiegand, Susanna %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Witteman, Jacqueline C %A Xu, Jianfeng %A Zhang, Qunyuan %A Zgaga, Lina %A Ziegler, Andreas %A Zitting, Paavo %A Beilby, John P %A Farooqi, I Sadaf %A Hebebrand, Johannes %A Huikuri, Heikki V %A James, Alan L %A Kähönen, Mika %A Levinson, Douglas F %A Macciardi, Fabio %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Ridker, Paul M %A Stumvoll, Michael %A Beckmann, Jacques S %A Boeing, Heiner %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Collins, Francis S %A Cupples, L Adrienne %A Smith, George Davey %A Erdmann, Jeanette %A Froguel, Philippe %A Grönberg, Henrik %A Gyllensten, Ulf %A Hall, Per %A Hansen, Torben %A Harris, Tamara B %A Hattersley, Andrew T %A Hayes, Richard B %A Heinrich, Joachim %A Hu, Frank B %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Kaprio, Jaakko %A Karpe, Fredrik %A Khaw, Kay-Tee %A Kiemeney, Lambertus A %A Krude, Heiko %A Laakso, Markku %A Lawlor, Debbie A %A Metspalu, Andres %A Munroe, Patricia B %A Ouwehand, Willem H %A Pedersen, Oluf %A Penninx, Brenda W %A Peters, Annette %A Pramstaller, Peter P %A Quertermous, Thomas %A Reinehr, Thomas %A Rissanen, Aila %A Rudan, Igor %A Samani, Nilesh J %A Schwarz, Peter E H %A Shuldiner, Alan R %A Spector, Timothy D %A Tuomilehto, Jaakko %A Uda, Manuela %A Uitterlinden, Andre %A Valle, Timo T %A Wabitsch, Martin %A Waeber, Gérard %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Wright, Alan F %A Zillikens, M Carola %A Chatterjee, Nilanjan %A McCarroll, Steven A %A Purcell, Shaun %A Schadt, Eric E %A Visscher, Peter M %A Assimes, Themistocles L %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Frayling, Timothy M %A Thorsteinsdottir, Unnur %A Abecasis, Goncalo R %A Barroso, Inês %A Boehnke, Michael %A Stefansson, Kari %A North, Kari E %A McCarthy, Mark I %A Hirschhorn, Joel N %A Ingelsson, Erik %A Loos, Ruth J F %K Body Height %K Body Mass Index %K Body Size %K Body Weight %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Obesity %K Polymorphism, Single Nucleotide %X

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.

%B Nat Genet %V 42 %P 937-48 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract %R 10.1038/ng.686 %0 Journal Article %J JAMA %D 2010 %T Association between adiposity in midlife and older age and risk of diabetes in older adults. %A Biggs, Mary L %A Mukamal, Kenneth J %A Luchsinger, José A %A Ix, Joachim H %A Carnethon, Mercedes R %A Newman, Anne B %A de Boer, Ian H %A Strotmeyer, Elsa S %A Mozaffarian, Dariush %A Siscovick, David S %K Adiposity %K Age Factors %K Aged %K Body Mass Index %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Incidence %K Male %K Prospective Studies %K Risk Factors %K United States %K Weight Gain %X

CONTEXT: Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults.

OBJECTIVE: To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older.

DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later.

MAIN OUTCOME MEASURE: Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater.

RESULTS: Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (+/-2 kg), those who gained the most weight from 50 years of age to baseline (> or = 9 kg), and from baseline to the third follow-up visit (> or = 6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less.

CONCLUSION: Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.

%B JAMA %V 303 %P 2504-12 %8 2010 Jun 23 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/20571017?dopt=Abstract %R 10.1001/jama.2010.843 %0 Journal Article %J Nephron Clin Pract %D 2010 %T Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study. %A Rifkin, Dena E %A Katz, Ronit %A Fried, Linda F %A Kestenbaum, Bryan %A Jenny, Nancy Swords %A Newman, Anne B %A Siscovick, David S %A Shlipak, Michael G %A Sarnak, Mark J %K Aged %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K Cross-Sectional Studies %K Female %K Follow-Up Studies %K Glomerular Filtration Rate %K Humans %K Kidney Function Tests %K Longitudinal Studies %K Male %K Residence Characteristics %X

BACKGROUND: In cross-sectional analyses, C-reactive protein (CRP) levels are inversely related to levels of kidney function. The relationship between kidney function and subsequent changes in CRP is unknown.

METHODS: We studied 4,364 individuals from the Cardiovascular Health Study, a longitudinal cohort of community-dwelling older adults. Baseline eGFRcys was estimated using cystatin C. CRP was measured at baseline and after 3 and 7 years of follow-up; slopes of change in CRP were calculated.

RESULTS: The mean (SD) age of the cohort was 72 (5.2) years; mean (SD) eGFRcys was 78.9 (18.4) ml/min/1.73 m(2). The median (interquartile range IQR) baseline CRP was 2.39 (1.22, 4.33) mg/l; the median (IQR) yearly change in CRP was -0.0051 (-0.020 to 0.27) mg/l/year. After adjustment for demographic characteristics and the initial level of CRP, each standard deviation lower baseline eGFR was associated with a small and non-significant yearly increase in CRP (0.032 mg/l/year; 95% CI: -0.005 to 0.070, p = 0.094).

CONCLUSIONS: We did not find a relationship between eGFR and subsequent changes in CRP. The association between kidney function and CRP in cross-sectional analyses may reflect unmeasured confounding by atherosclerosis; alternatively, the burden of comorbidity and interval mortality in this population may have masked a stronger longitudinal association between kidney function and change in CRP. Further study in younger populations may clarify whether impaired kidney function leads to change in inflammation over time.

%B Nephron Clin Pract %V 115 %P c114-21 %8 2010 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20413990?dopt=Abstract %R 10.1159/000312874 %0 Journal Article %J J Electrocardiol %D 2010 %T Association of Holter-based measures including T-wave alternans with risk of sudden cardiac death in the community-dwelling elderly: the Cardiovascular Health Study. %A Stein, Phyllis K %A Sanghavi, Devang %A Sotoodehnia, Nona %A Siscovick, David S %A Gottdiener, John %K Comorbidity %K Coronary Artery Disease %K Death, Sudden, Cardiac %K Electrocardiography, Ambulatory %K Female %K Humans %K Male %K Prevalence %K Prognosis %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sensitivity and Specificity %K Survival Analysis %K Survival Rate %K United States %K Ventricular Premature Complexes %X

BACKGROUND: Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher/lower risk is critical.

METHODS: The Cardiovascular Health Study is a population-based study of risk factors for coronary heart disease and stroke those 65 years or older. Forty-nine (of 1649) with usable Holters and in normal sinus rhythm had SCD during follow-up and were matched with 2 controls, alive at the time of death of the case and not experiencing SCD on follow-up. Univariate and multivariate conditional logistic regression determined the association of Holter-based information and SCD.

RESULTS: In univariate models, the upper half of ventricular premature contraction (VPC) counts, abnormal heart rate turbulence, decreased normalized low-frequency power, increased T-wave alternans (TWA), and decreased the short-term fractal scaling exponent (DFA(1)) were associated with SCD, but time domain heart rate variability was not. In multivariate models, the upper half of VPC counts (odds ratio [OR], 6.6) and having TWA of 37 muV or greater on channel 2 (OR, 4.8) were independently associated with SCD. Also, the upper half of VPC counts (OR, 6.9) and having a DFA(1) of less than 1.05 (OR, 5.0) were independently associated with SCD. When additive effects were explored, having both higher VPCs and higher TWA was associated with an OR of 8.2 for SCD compared with 2.6 for having either. Also, having both higher VPCs and lower DFA(1) was associated with an OR of 9.6 for SCD compared with 3.1 for having either.

CONCLUSIONS: Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.

%B J Electrocardiol %V 43 %P 251-9 %8 2010 May-Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20096853?dopt=Abstract %R 10.1016/j.jelectrocard.2009.12.009 %0 Journal Article %J Am J Clin Nutr %D 2010 %T Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. %A Mozaffarian, Dariush %A Cao, Haiming %A King, Irena B %A Lemaitre, Rozenn N %A Song, Xiaoling %A Siscovick, David S %A Hotamisligil, Gökhan S %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Body Mass Index %K Cholesterol %K Cholesterol, HDL %K Diabetes Mellitus %K Diet %K Dietary Carbohydrates %K Fatty Acids, Monounsaturated %K Female %K Fibrinogen %K Humans %K Insulin Resistance %K Life Style %K Lipids %K Male %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Sex Factors %K Triglycerides %X

BACKGROUND: Animal experiments suggest that circulating palmitoleic acid (cis-16:1n-7) from adipocyte de novo fatty acid synthesis may directly regulate insulin resistance and metabolic dysregulation.

OBJECTIVE: We investigated the independent determinants of circulating palmitoleate in free-living humans and whether palmitoleate is related to lower metabolic risk and the incidence of diabetes.

DESIGN: In a prospective cohort of 3630 US men and women in the Cardiovascular Health Study, plasma phospholipid fatty acids, anthropometric variables, blood lipids, inflammatory markers, and glucose and insulin concentrations were measured between 1992 and 2006 by using standardized methods. Independent determinants of plasma phospholipid palmitoleate and relations of palmitoleate with metabolic risk factors were investigated by using multivariable-adjusted linear regression. Relations with incident diabetes (296 incident cases) were investigated by using Cox proportional hazards.

RESULTS: The mean (± SD) palmitoleate value was 0.49 ± 0.20% (range: 0.11-2.55%) of total fatty acids. Greater body mass index, carbohydrate intake, protein intake, and alcohol use were each independent lifestyle correlates of higher palmitoleate concentrations. In multivariable analyses that adjusted for these factors and other potential confounders, higher palmitoleate concentrations were independently associated with lower LDL cholesterol (P < 0.001), higher HDL cholesterol (P < 0.001), lower total:HDL-cholesterol ratio (P = 0.04), and lower fibrinogen (P < 0.001). However, palmitoleate was also associated with higher triglycerides (P < 0.001) and (in men only) with greater insulin resistance (P < 0.001). Palmitoleate was not significantly associated with incident diabetes.

CONCLUSIONS: Adiposity (energy imbalance), carbohydrate consumption, and alcohol use-even within typical ranges-are associated with higher circulating palmitoleate concentrations. Circulating palmitoleate is robustly associated with multiple metabolic risk factors but in mixed directions, perhaps related to divergent lifestyle determinants or endogenous sources (liver, adipose tissue) of fatty acid synthesis.

%B Am J Clin Nutr %V 92 %P 1350-8 %8 2010 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20943795?dopt=Abstract %R 10.3945/ajcn.110.003970 %0 Journal Article %J Lancet %D 2010 %T Common genetic determinants of vitamin D insufficiency: a genome-wide association study. %A Wang, Thomas J %A Zhang, Feng %A Richards, J Brent %A Kestenbaum, Bryan %A van Meurs, Joyce B %A Berry, Diane %A Kiel, Douglas P %A Streeten, Elizabeth A %A Ohlsson, Claes %A Koller, Daniel L %A Peltonen, Leena %A Cooper, Jason D %A O'Reilly, Paul F %A Houston, Denise K %A Glazer, Nicole L %A Vandenput, Liesbeth %A Peacock, Munro %A Shi, Julia %A Rivadeneira, Fernando %A McCarthy, Mark I %A Anneli, Pouta %A de Boer, Ian H %A Mangino, Massimo %A Kato, Bernet %A Smyth, Deborah J %A Booth, Sarah L %A Jacques, Paul F %A Burke, Greg L %A Goodarzi, Mark %A Cheung, Ching-Lung %A Wolf, Myles %A Rice, Kenneth %A Goltzman, David %A Hidiroglou, Nick %A Ladouceur, Martin %A Wareham, Nicholas J %A Hocking, Lynne J %A Hart, Deborah %A Arden, Nigel K %A Cooper, Cyrus %A Malik, Suneil %A Fraser, William D %A Hartikainen, Anna-Liisa %A Zhai, Guangju %A Macdonald, Helen M %A Forouhi, Nita G %A Loos, Ruth J F %A Reid, David M %A Hakim, Alan %A Dennison, Elaine %A Liu, Yongmei %A Power, Chris %A Stevens, Helen E %A Jaana, Laitinen %A Vasan, Ramachandran S %A Soranzo, Nicole %A Bojunga, Jörg %A Psaty, Bruce M %A Lorentzon, Mattias %A Foroud, Tatiana %A Harris, Tamara B %A Hofman, Albert %A Jansson, John-Olov %A Cauley, Jane A %A Uitterlinden, André G %A Gibson, Quince %A Jarvelin, Marjo-Riitta %A Karasik, David %A Siscovick, David S %A Econs, Michael J %A Kritchevsky, Stephen B %A Florez, Jose C %A Todd, John A %A Dupuis, Josée %A Hyppönen, Elina %A Spector, Timothy D %K Canada %K Chromosomes, Human, Pair 11 %K Chromosomes, Human, Pair 4 %K Cohort Studies %K Dietary Supplements %K Europe %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Homozygote %K Humans %K Immunoassay %K International Cooperation %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Seasons %K United States %K Vitamin D %K Vitamin D Deficiency %X

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).

%B Lancet %V 376 %P 180-8 %8 2010 Jul 17 %G eng %N 9736 %1 http://www.ncbi.nlm.nih.gov/pubmed/20541252?dopt=Abstract %R 10.1016/S0140-6736(10)60588-0 %0 Journal Article %J J Am Soc Nephrol %D 2010 %T Common genetic variants associate with serum phosphorus concentration. %A Kestenbaum, Bryan %A Glazer, Nicole L %A Köttgen, Anna %A Felix, Janine F %A Hwang, Shih-Jen %A Liu, Yongmei %A Lohman, Kurt %A Kritchevsky, Stephen B %A Hausman, Dorothy B %A Petersen, Ann-Kristin %A Gieger, Christian %A Ried, Janina S %A Meitinger, Thomas %A Strom, Tim M %A Wichmann, H Erich %A Campbell, Harry %A Hayward, Caroline %A Rudan, Igor %A de Boer, Ian H %A Psaty, Bruce M %A Rice, Kenneth M %A Chen, Yii-Der Ida %A Li, Man %A Arking, Dan E %A Boerwinkle, Eric %A Coresh, Josef %A Yang, Qiong %A Levy, Daniel %A van Rooij, Frank J A %A Dehghan, Abbas %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A van Duijn, Cornelia M %A Shlipak, Michael G %A Kao, W H Linda %A Witteman, Jacqueline C M %A Siscovick, David S %A Fox, Caroline S %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Fibroblast Growth Factors %K Gene Frequency %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Male %K Middle Aged %K Phosphorus %K Polymorphism, Single Nucleotide %K Receptors, Calcium-Sensing %K Sex Factors %K Sodium-Phosphate Cotransporter Proteins, Type IIa %X

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.

%B J Am Soc Nephrol %V 21 %P 1223-32 %8 2010 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract %R 10.1681/ASN.2009111104 %0 Journal Article %J Nat Genet %D 2010 %T Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. %A Sotoodehnia, Nona %A Isaacs, Aaron %A de Bakker, Paul I W %A Dörr, Marcus %A Newton-Cheh, Christopher %A Nolte, Ilja M %A van der Harst, Pim %A Müller, Martina %A Eijgelsheim, Mark %A Alonso, Alvaro %A Hicks, Andrew A %A Padmanabhan, Sandosh %A Hayward, Caroline %A Smith, Albert Vernon %A Polasek, Ozren %A Giovannone, Steven %A Fu, Jingyuan %A Magnani, Jared W %A Marciante, Kristin D %A Pfeufer, Arne %A Gharib, Sina A %A Teumer, Alexander %A Li, Man %A Bis, Joshua C %A Rivadeneira, Fernando %A Aspelund, Thor %A Köttgen, Anna %A Johnson, Toby %A Rice, Kenneth %A Sie, Mark P S %A Wang, Ying A %A Klopp, Norman %A Fuchsberger, Christian %A Wild, Sarah H %A Mateo Leach, Irene %A Estrada, Karol %A Völker, Uwe %A Wright, Alan F %A Asselbergs, Folkert W %A Qu, Jiaxiang %A Chakravarti, Aravinda %A Sinner, Moritz F %A Kors, Jan A %A Petersmann, Astrid %A Harris, Tamara B %A Soliman, Elsayed Z %A Munroe, Patricia B %A Psaty, Bruce M %A Oostra, Ben A %A Cupples, L Adrienne %A Perz, Siegfried %A de Boer, Rudolf A %A Uitterlinden, André G %A Völzke, Henry %A Spector, Timothy D %A Liu, Fang-Yu %A Boerwinkle, Eric %A Dominiczak, Anna F %A Rotter, Jerome I %A van Herpen, Gé %A Levy, Daniel %A Wichmann, H-Erich %A van Gilst, Wiek H %A Witteman, Jacqueline C M %A Kroemer, Heyo K %A Kao, W H Linda %A Heckbert, Susan R %A Meitinger, Thomas %A Hofman, Albert %A Campbell, Harry %A Folsom, Aaron R %A van Veldhuisen, Dirk J %A Schwienbacher, Christine %A O'Donnell, Christopher J %A Volpato, Claudia Beu %A Caulfield, Mark J %A Connell, John M %A Launer, Lenore %A Lu, Xiaowen %A Franke, Lude %A Fehrmann, Rudolf S N %A te Meerman, Gerard %A Groen, Harry J M %A Weersma, Rinse K %A van den Berg, Leonard H %A Wijmenga, Cisca %A Ophoff, Roel A %A Navis, Gerjan %A Rudan, Igor %A Snieder, Harold %A Wilson, James F %A Pramstaller, Peter P %A Siscovick, David S %A Wang, Thomas J %A Gudnason, Vilmundur %A van Duijn, Cornelia M %A Felix, Stephan B %A Fishman, Glenn I %A Jamshidi, Yalda %A Stricker, Bruno H Ch %A Samani, Nilesh J %A Kääb, Stefan %A Arking, Dan E %K Animals %K Animals, Newborn %K Chromosomes, Human %K Computational Biology %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Mice %K Mice, Transgenic %K Models, Animal %K Myocytes, Cardiac %K NAV1.8 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Sodium Channels %X

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

%B Nat Genet %V 42 %P 1068-76 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21076409?dopt=Abstract %R 10.1038/ng.716 %0 Journal Article %J Hum Mol Genet %D 2010 %T Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. %A O'Seaghdha, Conall M %A Yang, Qiong %A Glazer, Nicole L %A Leak, Tennille S %A Dehghan, Abbas %A Smith, Albert V %A Kao, W H Linda %A Lohman, Kurt %A Hwang, Shih-Jen %A Johnson, Andrew D %A Hofman, Albert %A Uitterlinden, André G %A Chen, Yii-Der Ida %A Brown, Edward M %A Siscovick, David S %A Harris, Tamara B %A Psaty, Bruce M %A Coresh, Josef %A Gudnason, Vilmundur %A Witteman, Jacqueline C %A Liu, Yong Mei %A Kestenbaum, Bryan R %A Fox, Caroline S %A Köttgen, Anna %K Adult %K Calcium %K Female %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Calcium-Sensing %X

Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

%B Hum Mol Genet %V 19 %P 4296-303 %8 2010 Nov 01 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/20705733?dopt=Abstract %R 10.1093/hmg/ddq342 %0 Journal Article %J Respirology %D 2010 %T CRP gene variation and risk of community-acquired pneumonia. %A Mukamal, Kenneth J %A Pai, Jennifer K %A O'Meara, Ellen S %A Tracy, Russell P %A Psaty, Bruce M %A Kuller, Lewis H %A Newman, Anne B %A Yende, Sachin %A Curhan, Gary C %A Siscovick, David S %A Rimm, Eric B %K African Americans %K Aged %K Aged, 80 and over %K Body Mass Index %K C-Reactive Protein %K Cohort Studies %K Community-Acquired Infections %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Male %K Pneumonia %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Factors %K Smoking %X

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.

%B Respirology %V 15 %P 160-4 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/19947988?dopt=Abstract %R 10.1111/j.1440-1843.2009.01661.x %0 Journal Article %J Circ Cardiovasc Qual Outcomes %D 2010 %T Cystatin C and sudden cardiac death risk in the elderly. %A Deo, Rajat %A Sotoodehnia, Nona %A Katz, Ronit %A Sarnak, Mark J %A Fried, Linda F %A Chonchol, Michel %A Kestenbaum, Bryan %A Psaty, Bruce M %A Siscovick, David S %A Shlipak, Michael G %K Age Factors %K Aged %K Biomarkers %K Chi-Square Distribution %K Creatinine %K Cystatin C %K Death, Sudden, Cardiac %K Female %K Glomerular Filtration Rate %K Humans %K Incidence %K Kidney Diseases %K Longitudinal Studies %K Male %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Time Factors %K United States %K Up-Regulation %X

BACKGROUND: Recent studies have demonstrated an association between moderate kidney dysfunction and sudden cardiac death in people with cardiovascular disease.

METHODS AND RESULTS: The study was a longitudinal analysis among 4465 participants from the Cardiovascular Health Study without prevalent cardiovascular disease at baseline. Cystatin C and creatinine were measured from baseline sera. Sudden cardiac death (SCD) was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency room. The association between cystatin C tertiles and SCD was determined with multivariate Cox proportional hazards. A similar analysis compared SCD incidence across creatinine-based estimated glomerular filtration rate (eGFR) tertiles. Over a median follow-up of 11.2 years, 91 adjudicated SCD events occurred. The annual incidence of SCD events increased across cystatin C tertiles: 10 events per 10 000 person years in tertile 1, 25 events per 10 000 person years in tertile 2, and 32 events per 10 000 person-years in the highest cystatin C tertile. These associations persisted after multivariate adjustment: hazards ratio=2.72; 95% confidence interval, 1.44 to 5.16 in tertile 2 and hazards ratio=2.67; 95% confidence interval, 1.33 to 5.35 in tertile 3. After multivariate adjustment, the rate of SCD also increased in a linear distribution across creatinine-based eGFR tertiles: 15 events per 10 000 person-years in tertile 1, 22 events per 10 000 person-years in tertile 2, and 27 events per 10 000 person-years in tertile 3. No significant associations, however, remained between creatinine-based eGFR and SCD after multivariable adjustment.

CONCLUSIONS: Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.

%B Circ Cardiovasc Qual Outcomes %V 3 %P 159-64 %8 2010 Mar %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20233980?dopt=Abstract %R 10.1161/CIRCOUTCOMES.109.875369 %0 Journal Article %J J Bone Miner Res %D 2010 %T Fish consumption, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study. %A Virtanen, Jyrki K %A Mozaffarian, Dariush %A Cauley, Jane A %A Mukamal, Kenneth J %A Robbins, John %A Siscovick, David S %K Aged %K Aged, 80 and over %K Animals %K Bone Density %K Diet %K Female %K Fishes %K Hip Fractures %K Humans %K Male %K Risk Factors %K Surveys and Questionnaires %X

Marine n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be beneficial for bone health, but few studies have investigated the association with fish consumption. Our aim was to study associations of fish and EPA + DHA consumption with bone mineral density (BMD) and hip fracture risk and determine whether high linoleic acid (LA) intake, the major dietary n-6 PUFA, modifies the associations. The study population consisted of 5045 participants aged 65 years and older from the Cardiovascular Health Study. Data on BMD were available for 1305 participants. Food-frequency questionnaire was used to assess dietary intake, and hip fracture incidence was assessed prospectively by review of hospitalization records. After multivariable adjustment, femoral neck BMD was 0.01 g/cm(2) lower in the highest versus lowest tuna/other-fish intake category (p = .05 for trend). EPA + DHA intake (higher versus lower median of 0.32 g/day) was associated with lower femoral neck BMD (0.66 versus 0.71 g/cm(2), p < .001) among those with LA intake greater than the median 12.1 g/day (p = .03 for interaction). No significant associations were found with total-hip BMD. During mean follow-up of 11.1 years, 505 hip fractures occurred. Fish or EPA + DHA consumption was not significantly associated with fracture incidence [hazard ratio (HR) for extreme categories: HR = 1.23, 95% confidence interval (CI) 0.83-1.84 for tuna/other fish; HR = 1.16, 95% CI 0.91-1.49 for fried fish; and HR = 0.98, 95% CI 0.71-1.36 for EPA + DHA]. High LA intake did not modify these associations. In this large prospective cohort of older adults, fish consumption was associated with very small differences in BMD and had no association with hip fracture risk.

%B J Bone Miner Res %V 25 %P 1972-9 %8 2010 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20572022?dopt=Abstract %R 10.1002/jbmr.87 %0 Journal Article %J Am J Clin Nutr %D 2010 %T Food sources of individual plasma phospholipid trans fatty acid isomers: the Cardiovascular Health Study. %A Micha, Renata %A King, Irena B %A Lemaitre, Rozenn N %A Rimm, Eric B %A Sacks, Frank %A Song, Xiaoling %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Cardiovascular System %K Diet %K Diet Surveys %K Dietary Fats %K Female %K Food Analysis %K Health %K Humans %K Hydrogenation %K Isomerism %K Male %K Phospholipids %K Plant Oils %K Regression Analysis %K Surveys and Questionnaires %K Trans Fatty Acids %X

BACKGROUND: The overall consumption of trans fatty acids (TFAs) increases the risk of coronary artery disease. However, multiple TFA isomers exist, each with potentially different health effects. Different food sources of these specific TFA isomers are not well established.

OBJECTIVE: Our objective was to determine the major independent food sources of specific TFA isomers.

DESIGN: We investigated relations of major potential food sources of TFAs, as assessed by serial food-frequency questionnaires, with 10 plasma phospholipid TFA isomers [5 trans (t-) 18:1, 3 t-18:2, and 2 t-16:1] in 3330 older adults in the Cardiovascular Health Study, a community-based multicenter cohort. Stepwise regression was used to identify independent major food sources of individual plasma phospholipid TFA isomers, which were adjusted for demographic, lifestyle, and dietary factors.

RESULTS: All 5 t-18:1 isomers were similarly associated with foods commonly made with partially hydrogenated vegetable oils (PHVOs), including biscuits (0.51 higher SD of total 18:1 fatty acid concentrations per serving/d, P < 0.01), chips and/or popcorn (0.33 higher SD per serving/d, P = 0.02), margarine (0.32 higher SD per serving/d, P < 0.001), fried foods (0.32 higher SD per serving/d, P = 0.04), and bakery foods (0.23 higher SD per serving/d, P = 0.02). Each of the t-18:2 isomers were associated only with bakery foods (0.50 higher SD of total 18:2 fatty acid concentrations per serving/d, P < 0.001). Ruminant foods were major correlates of t-16:1n-7, including red meats (0.72 higher SD per serving/d, P < 0.001), butter (0.43 higher SD per serving/d, P < 0.001), and higher-fat dairy (0.37 higher SD per serving/d, P < 0.001). In contrast, t-16:1n-9 were derived mainly from margarine (0.31 higher SD per serving/d, P < 0.001).

CONCLUSIONS: t-18:1 Isomers are similarly derived from multiple PHVO-containing foods. In contrast, t-18:2 and t-16:1n-9 isomers are derived from more-specific types of PHVO-containing foods. Ruminant foods are major sources of t-16:1n-7. Different TFA isomers and dietary sources should be considered when investigating health effects and interventions to lower TFAs.

%B Am J Clin Nutr %V 91 %P 883-93 %8 2010 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20219966?dopt=Abstract %R 10.3945/ajcn.2009.28877 %0 Journal Article %J PLoS Genet %D 2010 %T Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. %A Ikram, M Kamran %A Sim, Xueling %A Xueling, Sim %A Jensen, Richard A %A Cotch, Mary Frances %A Hewitt, Alex W %A Ikram, M Arfan %A Wang, Jie Jin %A Klein, Ronald %A Klein, Barbara E K %A Breteler, Monique M B %A Cheung, Ning %A Liew, Gerald %A Mitchell, Paul %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A de Jong, Paulus T V M %A van Duijn, Cornelia M %A Kao, Linda %A Cheng, Ching-Yu %A Smith, Albert Vernon %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Jonasson, Fridbert %A Eiriksdottir, Gudny %A Aspelund, Thor %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Li, Xiaohui %A Iyengar, Sudha K %A Xi, Quansheng %A Sivakumaran, Theru A %A Mackey, David A %A Macgregor, Stuart %A Martin, Nicholas G %A Young, Terri L %A Bis, Josh C %A Wiggins, Kerri L %A Heckbert, Susan R %A Hammond, Christopher J %A Andrew, Toby %A Fahy, Samantha %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Islam, F M Amirul %A Rotter, Jerome I %A McAuley, Annie K %A Boerwinkle, Eric %A Tai, E Shyong %A Gudnason, Vilmundur %A Siscovick, David S %A Vingerling, Johannes R %A Wong, Tien Y %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Child %K Child, Preschool %K Chromosomes, Human, Pair 12 %K Chromosomes, Human, Pair 19 %K Chromosomes, Human, Pair 5 %K Chromosomes, Human, Pair 6 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Microcirculation %K Middle Aged %K Polymorphism, Single Nucleotide %K Retinal Vessels %K Young Adult %X

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.

%B PLoS Genet %V 6 %P e1001184 %8 2010 Oct 28 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract %R 10.1371/journal.pgen.1001184 %0 Journal Article %J Hum Mol Genet %D 2010 %T Genome-wide association analysis identifies multiple loci related to resting heart rate. %A Eijgelsheim, Mark %A Newton-Cheh, Christopher %A Sotoodehnia, Nona %A de Bakker, Paul I W %A Müller, Martina %A Morrison, Alanna C %A Smith, Albert V %A Isaacs, Aaron %A Sanna, Serena %A Dörr, Marcus %A Navarro, Pau %A Fuchsberger, Christian %A Nolte, Ilja M %A de Geus, Eco J C %A Estrada, Karol %A Hwang, Shih-Jen %A Bis, Joshua C %A Rückert, Ina-Maria %A Alonso, Alvaro %A Launer, Lenore J %A Hottenga, Jouke Jan %A Rivadeneira, Fernando %A Noseworthy, Peter A %A Rice, Kenneth M %A Perz, Siegfried %A Arking, Dan E %A Spector, Tim D %A Kors, Jan A %A Aulchenko, Yurii S %A Tarasov, Kirill V %A Homuth, Georg %A Wild, Sarah H %A Marroni, Fabio %A Gieger, Christian %A Licht, Carmilla M %A Prineas, Ronald J %A Hofman, Albert %A Rotter, Jerome I %A Hicks, Andrew A %A Ernst, Florian %A Najjar, Samer S %A Wright, Alan F %A Peters, Annette %A Fox, Ervin R %A Oostra, Ben A %A Kroemer, Heyo K %A Couper, David %A Völzke, Henry %A Campbell, Harry %A Meitinger, Thomas %A Uda, Manuela %A Witteman, Jacqueline C M %A Psaty, Bruce M %A Wichmann, H-Erich %A Harris, Tamara B %A Kääb, Stefan %A Siscovick, David S %A Jamshidi, Yalda %A Uitterlinden, André G %A Folsom, Aaron R %A Larson, Martin G %A Wilson, James F %A Penninx, Brenda W %A Snieder, Harold %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Lakatta, Edward G %A Felix, Stephan B %A Gudnason, Vilmundur %A Pfeufer, Arne %A Heckbert, Susan R %A Stricker, Bruno H Ch %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Adult %K Aged %K Base Pairing %K Cohort Studies %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Heart Rate %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Rest %X

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

%B Hum Mol Genet %V 19 %P 3885-94 %8 2010 Oct 01 %G eng %N 19 %1 http://www.ncbi.nlm.nih.gov/pubmed/20639392?dopt=Abstract %R 10.1093/hmg/ddq303 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide association identifies multiple ulcerative colitis susceptibility loci. %A McGovern, Dermot P B %A Gardet, Agnès %A Törkvist, Leif %A Goyette, Philippe %A Essers, Jonah %A Taylor, Kent D %A Neale, Benjamin M %A Ong, Rick T H %A Lagacé, Caroline %A Li, Chun %A Green, Todd %A Stevens, Christine R %A Beauchamp, Claudine %A Fleshner, Phillip R %A Carlson, Marie %A D'Amato, Mauro %A Halfvarson, Jonas %A Hibberd, Martin L %A Lördal, Mikael %A Padyukov, Leonid %A Andriulli, Angelo %A Colombo, Elisabetta %A Latiano, Anna %A Palmieri, Orazio %A Bernard, Edmond-Jean %A Deslandres, Colette %A Hommes, Daan W %A de Jong, Dirk J %A Stokkers, Pieter C %A Weersma, Rinse K %A Sharma, Yashoda %A Silverberg, Mark S %A Cho, Judy H %A Wu, Jing %A Roeder, Kathryn %A Brant, Steven R %A Schumm, L Phillip %A Duerr, Richard H %A Dubinsky, Marla C %A Glazer, Nicole L %A Haritunians, Talin %A Ippoliti, Andy %A Melmed, Gil Y %A Siscovick, David S %A Vasiliauskas, Eric A %A Targan, Stephan R %A Annese, Vito %A Wijmenga, Cisca %A Pettersson, Sven %A Rotter, Jerome I %A Xavier, Ramnik J %A Daly, Mark J %A Rioux, John D %A Seielstad, Mark %K Colitis, Ulcerative %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Membrane Proteins %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Receptors, IgG %X

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

%B Nat Genet %V 42 %P 332-7 %8 2010 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20228799?dopt=Abstract %R 10.1038/ng.549 %0 Journal Article %J PLoS Genet %D 2010 %T Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. %A Meyer, Tamra E %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Glazer, Nicole L %A Smith, Albert V %A van Rooij, Frank J A %A Ehret, Georg B %A Boerwinkle, Eric %A Felix, Janine F %A Leak, Tennille S %A Harris, Tamara B %A Yang, Qiong %A Dehghan, Abbas %A Aspelund, Thor %A Katz, Ronit %A Homuth, Georg %A Kocher, Thomas %A Rettig, Rainer %A Ried, Janina S %A Gieger, Christian %A Prucha, Hanna %A Pfeufer, Arne %A Meitinger, Thomas %A Coresh, Josef %A Hofman, Albert %A Sarnak, Mark J %A Chen, Yii-Der Ida %A Uitterlinden, André G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %A Kao, W H Linda %A Witteman, Jacqueline C M %A Gudnason, Vilmundur %A Siscovick, David S %A Fox, Caroline S %A Köttgen, Anna %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Magnesium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Potassium %K Sodium %X

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.

%B PLoS Genet %V 6 %8 2010 Aug 05 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract %R 10.1371/journal.pgen.1001045 %0 Journal Article %J PLoS One %D 2010 %T Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. %A Arking, Dan E %A Reinier, Kyndaron %A Post, Wendy %A Jui, Jonathan %A Hilton, Gina %A O'Connor, Ashley %A Prineas, Ronald J %A Boerwinkle, Eric %A Psaty, Bruce M %A Tomaselli, Gordon F %A Rea, Thomas %A Sotoodehnia, Nona %A Siscovick, David S %A Burke, Gregory L %A Marbán, Eduardo %A Spooner, Peter M %A Chakravarti, Aravinda %A Chugh, Sumeet S %K Aged %K Alleles %K Case-Control Studies %K Cohort Studies %K Death, Sudden, Cardiac %K Ethnic Groups %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glypicans %K Heart Diseases %K Humans %K Male %K Middle Aged %K Models, Genetic %K Oligonucleotide Array Sequence Analysis %K Oregon %K Polymorphism, Single Nucleotide %X

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

%B PLoS One %V 5 %P e9879 %8 2010 Mar 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20360844?dopt=Abstract %R 10.1371/journal.pone.0009879 %0 Journal Article %J Nature %D 2010 %T Hundreds of variants clustered in genomic loci and biological pathways affect human height. %A Lango Allen, Hana %A Estrada, Karol %A Lettre, Guillaume %A Berndt, Sonja I %A Weedon, Michael N %A Rivadeneira, Fernando %A Willer, Cristen J %A Jackson, Anne U %A Vedantam, Sailaja %A Raychaudhuri, Soumya %A Ferreira, Teresa %A Wood, Andrew R %A Weyant, Robert J %A Segrè, Ayellet V %A Speliotes, Elizabeth K %A Wheeler, Eleanor %A Soranzo, Nicole %A Park, Ju-Hyun %A Yang, Jian %A Gudbjartsson, Daniel %A Heard-Costa, Nancy L %A Randall, Joshua C %A Qi, Lu %A Vernon Smith, Albert %A Mägi, Reedik %A Pastinen, Tomi %A Liang, Liming %A Heid, Iris M %A Luan, Jian'an %A Thorleifsson, Gudmar %A Winkler, Thomas W %A Goddard, Michael E %A Sin Lo, Ken %A Palmer, Cameron %A Workalemahu, Tsegaselassie %A Aulchenko, Yurii S %A Johansson, Asa %A Zillikens, M Carola %A Feitosa, Mary F %A Esko, Tõnu %A Johnson, Toby %A Ketkar, Shamika %A Kraft, Peter %A Mangino, Massimo %A Prokopenko, Inga %A Absher, Devin %A Albrecht, Eva %A Ernst, Florian %A Glazer, Nicole L %A Hayward, Caroline %A Hottenga, Jouke-Jan %A Jacobs, Kevin B %A Knowles, Joshua W %A Kutalik, Zoltán %A Monda, Keri L %A Polasek, Ozren %A Preuss, Michael %A Rayner, Nigel W %A Robertson, Neil R %A Steinthorsdottir, Valgerdur %A Tyrer, Jonathan P %A Voight, Benjamin F %A Wiklund, Fredrik %A Xu, Jianfeng %A Zhao, Jing Hua %A Nyholt, Dale R %A Pellikka, Niina %A Perola, Markus %A Perry, John R B %A Surakka, Ida %A Tammesoo, Mari-Liis %A Altmaier, Elizabeth L %A Amin, Najaf %A Aspelund, Thor %A Bhangale, Tushar %A Boucher, Gabrielle %A Chasman, Daniel I %A Chen, Constance %A Coin, Lachlan %A Cooper, Matthew N %A Dixon, Anna L %A Gibson, Quince %A Grundberg, Elin %A Hao, Ke %A Juhani Junttila, M %A Kaplan, Lee M %A Kettunen, Johannes %A König, Inke R %A Kwan, Tony %A Lawrence, Robert W %A Levinson, Douglas F %A Lorentzon, Mattias %A McKnight, Barbara %A Morris, Andrew P %A Müller, Martina %A Suh Ngwa, Julius %A Purcell, Shaun %A Rafelt, Suzanne %A Salem, Rany M %A Salvi, Erika %A Sanna, Serena %A Shi, Jianxin %A Sovio, Ulla %A Thompson, John R %A Turchin, Michael C %A Vandenput, Liesbeth %A Verlaan, Dominique J %A Vitart, Veronique %A White, Charles C %A Ziegler, Andreas %A Almgren, Peter %A Balmforth, Anthony J %A Campbell, Harry %A Citterio, Lorena %A De Grandi, Alessandro %A Dominiczak, Anna %A Duan, Jubao %A Elliott, Paul %A Elosua, Roberto %A Eriksson, Johan G %A Freimer, Nelson B %A Geus, Eco J C %A Glorioso, Nicola %A Haiqing, Shen %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Illig, Thomas %A Jula, Antti %A Kajantie, Eero %A Kilpeläinen, Tuomas O %A Koiranen, Markku %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Laitinen, Jaana %A Liu, Jianjun %A Lokki, Marja-Liisa %A Marusic, Ana %A Maschio, Andrea %A Meitinger, Thomas %A Mulas, Antonella %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Petersmann, Astrid %A Pichler, Irene %A Pietiläinen, Kirsi H %A Pouta, Anneli %A Ridderstråle, Martin %A Rotter, Jerome I %A Sambrook, Jennifer G %A Sanders, Alan R %A Schmidt, Carsten Oliver %A Sinisalo, Juha %A Smit, Jan H %A Stringham, Heather M %A Bragi Walters, G %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Zagato, Laura %A Zgaga, Lina %A Zitting, Paavo %A Alavere, Helene %A Farrall, Martin %A McArdle, Wendy L %A Nelis, Mari %A Peters, Marjolein J %A Ripatti, Samuli %A van Meurs, Joyce B J %A Aben, Katja K %A Ardlie, Kristin G %A Beckmann, Jacques S %A Beilby, John P %A Bergman, Richard N %A Bergmann, Sven %A Collins, Francis S %A Cusi, Daniele %A den Heijer, Martin %A Eiriksdottir, Gudny %A Gejman, Pablo V %A Hall, Alistair S %A Hamsten, Anders %A Huikuri, Heikki V %A Iribarren, Carlos %A Kähönen, Mika %A Kaprio, Jaakko %A Kathiresan, Sekar %A Kiemeney, Lambertus %A Kocher, Thomas %A Launer, Lenore J %A Lehtimäki, Terho %A Melander, Olle %A Mosley, Tom H %A Musk, Arthur W %A Nieminen, Markku S %A O'Donnell, Christopher J %A Ohlsson, Claes %A Oostra, Ben %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Rioux, John D %A Rissanen, Aila %A Rivolta, Carlo %A Schunkert, Heribert %A Shuldiner, Alan R %A Siscovick, David S %A Stumvoll, Michael %A Tönjes, Anke %A Tuomilehto, Jaakko %A van Ommen, Gert-Jan %A Viikari, Jorma %A Heath, Andrew C %A Martin, Nicholas G %A Montgomery, Grant W %A Province, Michael A %A Kayser, Manfred %A Arnold, Alice M %A Atwood, Larry D %A Boerwinkle, Eric %A Chanock, Stephen J %A Deloukas, Panos %A Gieger, Christian %A Grönberg, Henrik %A Hall, Per %A Hattersley, Andrew T %A Hengstenberg, Christian %A Hoffman, Wolfgang %A Lathrop, G Mark %A Salomaa, Veikko %A Schreiber, Stefan %A Uda, Manuela %A Waterworth, Dawn %A Wright, Alan F %A Assimes, Themistocles L %A Barroso, Inês %A Hofman, Albert %A Mohlke, Karen L %A Boomsma, Dorret I %A Caulfield, Mark J %A Cupples, L Adrienne %A Erdmann, Jeanette %A Fox, Caroline S %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hayes, Richard B %A Jarvelin, Marjo-Riitta %A Mooser, Vincent %A Munroe, Patricia B %A Ouwehand, Willem H %A Penninx, Brenda W %A Pramstaller, Peter P %A Quertermous, Thomas %A Rudan, Igor %A Samani, Nilesh J %A Spector, Timothy D %A Völzke, Henry %A Watkins, Hugh %A Wilson, James F %A Groop, Leif C %A Haritunians, Talin %A Hu, Frank B %A Kaplan, Robert C %A Metspalu, Andres %A North, Kari E %A Schlessinger, David %A Wareham, Nicholas J %A Hunter, David J %A O'Connell, Jeffrey R %A Strachan, David P %A Wichmann, H-Erich %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Schadt, Eric E %A Thorsteinsdottir, Unnur %A Peltonen, Leena %A Uitterlinden, André G %A Visscher, Peter M %A Chatterjee, Nilanjan %A Loos, Ruth J F %A Boehnke, Michael %A McCarthy, Mark I %A Ingelsson, Erik %A Lindgren, Cecilia M %A Abecasis, Goncalo R %A Stefansson, Kari %A Frayling, Timothy M %A Hirschhorn, Joel N %K Body Height %K Chromosomes, Human, Pair 3 %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Metabolic Networks and Pathways %K Multifactorial Inheritance %K Phenotype %K Polymorphism, Single Nucleotide %X

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

%B Nature %V 467 %P 832-8 %8 2010 Oct 14 %G eng %N 7317 %1 http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract %R 10.1038/nature09410 %0 Journal Article %J J Card Fail %D 2010 %T Impaired kidney function and atrial fibrillation in elderly subjects. %A Deo, Rajat %A Katz, Ronit %A Kestenbaum, Bryan %A Fried, Linda %A Sarnak, Mark J %A Psaty, Bruce M %A Siscovick, David S %A Shlipak, Michael G %K Age Factors %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Cohort Studies %K Cross-Sectional Studies %K Female %K Follow-Up Studies %K Glomerular Filtration Rate %K Humans %K Kidney Diseases %K Kidney Function Tests %K Male %X

BACKGROUND: Impaired kidney function is associated with increased risk for cardiovascular events. We evaluated whether kidney function is associated with atrial fibrillation (AF) risk in elderly persons.

METHODS AND RESULTS: Subjects were participants in the Cardiovascular Health Study (CHS), a population-based cohort of ambulatory elderly. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). Among the 4663 participants, 342 (7%) had AF at baseline and 579 (13%) developed incident AF during follow-up (mean 7.4 years). In unadjusted analyses, cystatin C quartiles were strongly associated with prevalent AF with a nearly 3-fold odds in the highest quartile compared with the lowest (HR=1.19, 95% CI [0.80-1.76] in quartile 2; HR=2.00, 95% CI [1.38-2.88] in quartile 3; and HR=2.87, 95% CI [2.03-4.07] in quartile 4). This increased risk for prevalent AF remained significant after multivariate adjustment. The risk for incident AF increased across cystatin C quartiles in the unadjusted analysis (HR=1.37, 95% CI [1.07-1.75] in quartile 2; HR=1.43, 95% CI [1.11-1.84] in quartile 3; and HR=1.88, 95% CI [1.47-2.41] in quartile 4); however, after multivariate adjustment, these findings were no longer significant. An estimated GFR <60 mL.min.1.73m(2) was associated with prevalent and incident AF in unadjusted, but not multivariate analyses.

CONCLUSIONS: Impaired kidney function, as measured by cystatin C, is an independent marker of prevalent AF; however, neither cystatin C nor eGFR are predictors of incident AF.

%B J Card Fail %V 16 %P 55-60 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20123319?dopt=Abstract %R 10.1016/j.cardfail.2009.07.002 %0 Journal Article %J Diabetes Care %D 2010 %T 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. %A Nettleton, Jennifer A %A McKeown, Nicola M %A Kanoni, Stavroula %A Lemaitre, Rozenn N %A Hivert, Marie-France %A Ngwa, Julius %A van Rooij, Frank J A %A Sonestedt, Emily %A Wojczynski, Mary K %A Ye, Zheng %A Tanaka, Tosh %A Garcia, Melissa %A Anderson, Jennifer S %A Follis, Jack L %A Djoussé, Luc %A Mukamal, Kenneth %A Papoutsakis, Constantina %A Mozaffarian, Dariush %A Zillikens, M Carola %A Bandinelli, Stefania %A Bennett, Amanda J %A Borecki, Ingrid B %A Feitosa, Mary F %A Ferrucci, Luigi %A Forouhi, Nita G %A Groves, Christopher J %A Hallmans, Göran %A Harris, Tamara %A Hofman, Albert %A Houston, Denise K %A Hu, Frank B %A Johansson, Ingegerd %A Kritchevsky, Stephen B %A Langenberg, Claudia %A Launer, Lenore %A Liu, Yongmei %A Loos, Ruth J %A Nalls, Michael %A Orho-Melander, Marju %A Renstrom, Frida %A Rice, Kenneth %A Riserus, Ulf %A Rolandsson, Olov %A Rotter, Jerome I %A Saylor, Georgia %A Sijbrands, Eric J G %A Sjogren, Per %A Smith, Albert %A Steingrímsdóttir, Laufey %A Uitterlinden, André G %A Wareham, Nicholas J %A Prokopenko, Inga %A Pankow, James S %A van Duijn, Cornelia M %A Florez, Jose C %A Witteman, Jacqueline C M %A Dupuis, Josée %A Dedoussis, George V %A Ordovas, Jose M %A Ingelsson, Erik %A Cupples, L Adrienne %A Siscovick, David S %A Franks, Paul W %A Meigs, James B %K Adult %K Aged %K Blood Glucose %K Edible Grain %K European Continental Ancestry Group %K Fasting %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

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.

%B Diabetes Care %V 33 %P 2684-91 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20693352?dopt=Abstract %R 10.2337/dc10-1150 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. %A Yang, Qiong %A Köttgen, Anna %A Dehghan, Abbas %A Smith, Albert V %A Glazer, Nicole L %A Chen, Ming-Huei %A Chasman, Daniel I %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore %A Nalls, Michael %A Hernandez, Dena %A Arking, Dan E %A Boerwinkle, Eric %A Grove, Megan L %A Li, Man %A Linda Kao, W H %A Chonchol, Michel %A Haritunians, Talin %A Li, Guo %A Lumley, Thomas %A Psaty, Bruce M %A Shlipak, Michael %A Hwang, Shih-Jen %A Larson, Martin G %A O'Donnell, Christopher J %A Upadhyay, Ashish %A van Duijn, Cornelia M %A Hofman, Albert %A Rivadeneira, Fernando %A Stricker, Bruno %A Uitterlinden, André G %A Paré, Guillaume %A Parker, Alex N %A Ridker, Paul M %A Siscovick, David S %A Gudnason, Vilmundur %A Witteman, Jacqueline C %A Fox, Caroline S %A Coresh, Josef %K Cardiovascular Diseases %K Coronary Disease %K Female %K Genetic Loci %K Genome-Wide Association Study %K Gout %K Humans %K Male %K Risk Factors %K Uric Acid %X

BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

%B Circ Cardiovasc Genet %V 3 %P 523-30 %8 2010 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract %R 10.1161/CIRCGENETICS.109.934455 %0 Journal Article %J Nat Genet %D 2010 %T New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. %A Dupuis, Josée %A Langenberg, Claudia %A Prokopenko, Inga %A Saxena, Richa %A Soranzo, Nicole %A Jackson, Anne U %A Wheeler, Eleanor %A Glazer, Nicole L %A Bouatia-Naji, Nabila %A Gloyn, Anna L %A Lindgren, Cecilia M %A Mägi, Reedik %A Morris, Andrew P %A Randall, Joshua %A Johnson, Toby %A Elliott, Paul %A Rybin, Denis %A Thorleifsson, Gudmar %A Steinthorsdottir, Valgerdur %A Henneman, Peter %A Grallert, Harald %A Dehghan, Abbas %A Hottenga, Jouke Jan %A Franklin, Christopher S %A Navarro, Pau %A Song, Kijoung %A Goel, Anuj %A Perry, John R B %A Egan, Josephine M %A Lajunen, Taina %A Grarup, Niels %A Sparsø, Thomas %A Doney, Alex %A Voight, Benjamin F %A Stringham, Heather M %A Li, Man %A Kanoni, Stavroula %A Shrader, Peter %A Cavalcanti-Proença, Christine %A Kumari, Meena %A Qi, Lu %A Timpson, Nicholas J %A Gieger, Christian %A Zabena, Carina %A Rocheleau, Ghislain %A Ingelsson, Erik %A An, Ping %A O'Connell, Jeffrey %A Luan, Jian'an %A Elliott, Amanda %A McCarroll, Steven A %A Payne, Felicity %A Roccasecca, Rosa Maria %A Pattou, François %A Sethupathy, Praveen %A Ardlie, Kristin %A Ariyurek, Yavuz %A Balkau, Beverley %A Barter, Philip %A Beilby, John P %A Ben-Shlomo, Yoav %A Benediktsson, Rafn %A Bennett, Amanda J %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bonnefond, Amélie %A Bonnycastle, Lori L %A Borch-Johnsen, Knut %A Böttcher, Yvonne %A Brunner, Eric %A Bumpstead, Suzannah J %A Charpentier, Guillaume %A Chen, Yii-Der Ida %A Chines, Peter %A Clarke, Robert %A Coin, Lachlan J M %A Cooper, Matthew N %A Cornelis, Marilyn %A Crawford, Gabe %A Crisponi, Laura %A Day, Ian N M %A de Geus, Eco J C %A Delplanque, Jerome %A Dina, Christian %A Erdos, Michael R %A Fedson, Annette C %A Fischer-Rosinsky, Antje %A Forouhi, Nita G %A Fox, Caroline S %A Frants, Rune %A Franzosi, Maria Grazia %A Galan, Pilar %A Goodarzi, Mark O %A Graessler, Jürgen %A Groves, Christopher J %A Grundy, Scott %A Gwilliam, Rhian %A Gyllensten, Ulf %A Hadjadj, Samy %A Hallmans, Göran %A Hammond, Naomi %A Han, Xijing %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hayward, Caroline %A Heath, Simon C %A Hercberg, Serge %A Herder, Christian %A Hicks, Andrew A %A Hillman, David R %A Hingorani, Aroon D %A Hofman, Albert %A Hui, Jennie %A Hung, Joe %A Isomaa, Bo %A Johnson, Paul R V %A Jørgensen, Torben %A Jula, Antti %A Kaakinen, Marika %A Kaprio, Jaakko %A Kesaniemi, Y Antero %A Kivimaki, Mika %A Knight, Beatrice %A Koskinen, Seppo %A Kovacs, Peter %A Kyvik, Kirsten Ohm %A Lathrop, G Mark %A Lawlor, Debbie A %A Le Bacquer, Olivier %A Lecoeur, Cécile %A Li, Yun %A Lyssenko, Valeriya %A Mahley, Robert %A Mangino, Massimo %A Manning, Alisa K %A Martínez-Larrad, María Teresa %A McAteer, Jarred B %A McCulloch, Laura J %A McPherson, Ruth %A Meisinger, Christa %A Melzer, David %A Meyre, David %A Mitchell, Braxton D %A Morken, Mario A %A Mukherjee, Sutapa %A Naitza, Silvia %A Narisu, Narisu %A Neville, Matthew J %A Oostra, Ben A %A Orrù, Marco %A Pakyz, Ruth %A Palmer, Colin N A %A Paolisso, Giuseppe %A Pattaro, Cristian %A Pearson, Daniel %A Peden, John F %A Pedersen, Nancy L %A Perola, Markus %A Pfeiffer, Andreas F H %A Pichler, Irene %A Polasek, Ozren %A Posthuma, Danielle %A Potter, Simon C %A Pouta, Anneli %A Province, Michael A %A Psaty, Bruce M %A Rathmann, Wolfgang %A Rayner, Nigel W %A Rice, Kenneth %A Ripatti, Samuli %A Rivadeneira, Fernando %A Roden, Michael %A Rolandsson, Olov %A Sandbaek, Annelli %A Sandhu, Manjinder %A Sanna, Serena %A Sayer, Avan Aihie %A Scheet, Paul %A Scott, Laura J %A Seedorf, Udo %A Sharp, Stephen J %A Shields, Beverley %A Sigurethsson, Gunnar %A Sijbrands, Eric J G %A Silveira, Angela %A Simpson, Laila %A Singleton, Andrew %A Smith, Nicholas L %A Sovio, Ulla %A Swift, Amy %A Syddall, Holly %A Syvänen, Ann-Christine %A Tanaka, Toshiko %A Thorand, Barbara %A Tichet, Jean %A Tönjes, Anke %A Tuomi, Tiinamaija %A Uitterlinden, André G %A van Dijk, Ko Willems %A van Hoek, Mandy %A Varma, Dhiraj %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogelzangs, Nicole %A Waeber, Gérard %A Wagner, Peter J %A Walley, Andrew %A Walters, G Bragi %A Ward, Kim L %A Watkins, Hugh %A Weedon, Michael N %A Wild, Sarah H %A Willemsen, Gonneke %A Witteman, Jaqueline C M %A Yarnell, John W G %A Zeggini, Eleftheria %A Zelenika, Diana %A Zethelius, Björn %A Zhai, Guangju %A Zhao, Jing Hua %A Zillikens, M Carola %A Borecki, Ingrid B %A Loos, Ruth J F %A Meneton, Pierre %A Magnusson, Patrik K E %A Nathan, David M %A Williams, Gordon H %A Hattersley, Andrew T %A Silander, Kaisa %A Salomaa, Veikko %A Smith, George Davey %A Bornstein, Stefan R %A Schwarz, Peter %A Spranger, Joachim %A Karpe, Fredrik %A Shuldiner, Alan R %A Cooper, Cyrus %A Dedoussis, George V %A Serrano-Ríos, Manuel %A Morris, Andrew D %A Lind, Lars %A Palmer, Lyle J %A Hu, Frank B %A Franks, Paul W %A Ebrahim, Shah %A Marmot, Michael %A Kao, W H Linda %A Pankow, James S %A Sampson, Michael J %A Kuusisto, Johanna %A Laakso, Markku %A Hansen, Torben %A Pedersen, Oluf %A Pramstaller, Peter Paul %A Wichmann, H Erich %A Illig, Thomas %A Rudan, Igor %A Wright, Alan F %A Stumvoll, Michael %A Campbell, Harry %A Wilson, James F %A Bergman, Richard N %A Buchanan, Thomas A %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A Valle, Timo T %A Altshuler, David %A Rotter, Jerome I %A Siscovick, David S %A Penninx, Brenda W J H %A Boomsma, Dorret I %A Deloukas, Panos %A Spector, Timothy D %A Frayling, Timothy M %A Ferrucci, Luigi %A Kong, Augustine %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A van Duijn, Cornelia M %A Aulchenko, Yurii S %A Cao, Antonio %A Scuteri, Angelo %A Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Waterworth, Dawn M %A Vollenweider, Peter %A Peltonen, Leena %A Mooser, Vincent %A Abecasis, Goncalo R %A Wareham, Nicholas J %A Sladek, Robert %A Froguel, Philippe %A Watanabe, Richard M %A Meigs, James B %A Groop, Leif %A Boehnke, Michael %A McCarthy, Mark I %A Florez, Jose C %A Barroso, Inês %K Adolescent %K Adult %K Alleles %K Blood Glucose %K Child %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K DNA Copy Number Variations %K Fasting %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeostasis %K Humans %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Reproducibility of Results %X

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

%B Nat Genet %V 42 %P 105-16 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract %R 10.1038/ng.520 %0 Journal Article %J Diabetes Care %D 2010 %T Parity and the association with diabetes in older women. %A Fowler-Brown, Angela G %A de Boer, Ian H %A Catov, Janet M %A Carnethon, Mercedes R %A Kamineni, Aruna %A Kuller, Lewis H %A Siscovick, David S %A Mukamal, Kenneth J %K Aged %K Body Weight %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Humans %K Parity %K Pregnancy %K Socioeconomic Factors %X

OBJECTIVE: To examine the relationship of parity with diabetes and markers of glucose homeostasis in older women.

RESEARCH DESIGN AND METHODS: We used data from the female participants in the Cardiovascular Health Study, a longitudinal cohort of adults aged >or=65 years. These data included an assessment of parity (baseline) and fasting serum levels of glucose, insulin, and medication use (baseline and follow-up). We estimated both the cross-sectional relationship of parity with baseline diabetes and the relationship of parity with incident diabetes.

RESULTS: In unadjusted analyses, women with grand multiparity (>or=5 live births) had a higher prevalence of diabetes at baseline compared with those with fewer births and with nulliparous women (25 vs. 12 vs. 15%; P < 0.001). In regression models controlling for age and race, grand multiparity was associated with increased prevalence of diabetes (prevalence ratio 1.57 [95% CI 1.20-2.06]); with addition of demographic and clinical factors to the model, the association was attenuated (1.33 [1.00-1.77]). In final models that included body anthropometrics, the association was no longer significant (1.21 [0.86-1.49]). In those without diabetes at baseline, parity was not associated with incident diabetes or with fasting glucose; however, there was a modest association of parity with fasting insulin and homeostasis assessment model of insulin resistance.

CONCLUSIONS: Grand multiparity is associated with diabetes in elderly women in cross-sectional analyses. This relationship seems to be confounded and/or mediated by variation in body weight and sociodemographic factors by parity status. In older nondiabetic women, higher parity does not pose an ongoing risk of developing diabetes.

%B Diabetes Care %V 33 %P 1778-82 %8 2010 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20424225?dopt=Abstract %R 10.2337/dc10-0015 %0 Journal Article %J Ann Intern Med %D 2010 %T Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. %A Mozaffarian, Dariush %A Cao, Haiming %A King, Irena B %A Lemaitre, Rozenn N %A Song, Xiaoling %A Siscovick, David S %A Hotamisligil, Gökhan S %K Adiposity %K Aged %K C-Reactive Protein %K Cholesterol %K Cholesterol, HDL %K Dairy Products %K Diabetes Mellitus, Type 2 %K Fatty Acids, Monounsaturated %K Feeding Behavior %K Female %K Humans %K Incidence %K Insulin Resistance %K Male %K Prospective Studies %K Risk Factors %K Triglycerides %K United States %X

BACKGROUND: Palmitoleic acid (cis-16:1n-7), which is produced by endogenous fat synthesis, has been linked to both beneficial and deleterious metabolic effects, potentially confounded by diverse determinants and tissue sources of endogenous production. Trans-palmitoleate (trans-16:1n-7) represents a distinctly exogenous source of 16:1n-7, unconfounded by endogenous synthesis or its determinants, that may be uniquely informative.

OBJECTIVE: To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes.

DESIGN: Prospective cohort study from 1992 to 2006.

SETTING: Four U.S. communities.

PATIENTS: 3736 adults in the Cardiovascular Health Study.

MEASUREMENTS: Anthropometric characteristics and levels of plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose-insulin measured at baseline in 1992 and dietary habits measured 3 years earlier. Multivariate-adjusted models were used to investigate how demographic, clinical, and lifestyle factors independently related to plasma phospholipid trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). Findings were validated for metabolic risk factors in an independent cohort of 327 women.

RESULTS: In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels (1.9% across quintiles; P = 0.040), lower triglyceride levels (-19.0%; P < 0.001), a lower total cholesterol-HDL cholesterol ratio (-4.7%; P < 0.001), lower C-reactive protein levels (-13.8%; P = 0.05), and lower insulin resistance (-16.7%, P < 0.001). Trans-palmitoleate was also associated with a substantially lower incidence of diabetes, with multivariate hazard ratios of 0.41 (95% CI, 0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles 4 and 5 versus quintile 1 (P for trend < 0.001). Findings were independent of estimated dairy consumption or other fatty acid dairy biomarkers. Protective associations with metabolic risk factors were confirmed in the validation cohort.

LIMITATION: Results could be affected by measurement error or residual confounding.

CONCLUSION: Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

%B Ann Intern Med %V 153 %P 790-9 %8 2010 Dec 21 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21173413?dopt=Abstract %R 10.7326/0003-4819-153-12-201012210-00005 %0 Journal Article %J Am J Epidemiol %D 2011 %T Association of body mass index with peripheral arterial disease in older adults: the Cardiovascular Health Study. %A Ix, Joachim H %A Biggs, Mary L %A Kizer, Jorge R %A Mukamal, Kenneth J %A Djoussé, Luc %A Zieman, Susan J %A de Boer, Ian H %A Nelson, Tracy L %A Newman, Anne B %A Criqui, Michael H %A Siscovick, David S %K Aged %K Ankle Brachial Index %K Body Mass Index %K Cross-Sectional Studies %K Health Status %K Humans %K Kaplan-Meier Estimate %K Longitudinal Studies %K Male %K Obesity %K Peripheral Arterial Disease %K Prevalence %K Sex Factors %K Smoking %K United States %X

The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)(2)) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥ 65 years at baseline (1989-1990 or 1992-1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.

%B Am J Epidemiol %V 174 %P 1036-43 %8 2011 Nov 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21920948?dopt=Abstract %R 10.1093/aje/kwr228 %0 Journal Article %J J Am Coll Cardiol %D 2011 %T Association of serum phosphate levels with aortic valve sclerosis and annular calcification: the cardiovascular health study. %A Linefsky, Jason P %A O'Brien, Kevin D %A Katz, Ronit %A de Boer, Ian H %A Barasch, Eddy %A Jenny, Nancy S %A Siscovick, David S %A Kestenbaum, Bryan %K Aged %K Aortic Valve %K Calcinosis %K Calcium %K Female %K Heart Valve Diseases %K Humans %K Male %K Mitral Valve %K Parathyroid Hormone %K Phosphates %K Risk Factors %K Sclerosis %K Vitamin D %X

OBJECTIVES: This study was conducted to evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease.

BACKGROUND: Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults.

METHODS: We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiographic measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function.

RESULTS: The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with greater adjusted odds of AVS (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.04 to 1.31, p = 0.01), MAC (OR: 1.12, 95% CI: 1.00 to 1.26, p = 0.05), and AAC (OR: 1.12, 95% CI: 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification.

CONCLUSIONS: Higher serum phosphate levels within the normal range were associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.

%B J Am Coll Cardiol %V 58 %P 291-7 %8 2011 Jul 12 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21737022?dopt=Abstract %R 10.1016/j.jacc.2010.11.073 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2011 %T Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). %A Sobrin, Lucia %A Green, Todd %A Sim, Xueling %A Jensen, Richard A %A Tai, E Shyong %A Tay, Wan Ting %A Wang, Jie Jin %A Mitchell, Paul %A Sandholm, Niina %A Liu, Yiyuan %A Hietala, Kustaa %A Iyengar, Sudha K %A Brooks, Matthew %A Buraczynska, Monika %A Van Zuydam, Natalie %A Smith, Albert V %A Gudnason, Vilmundur %A Doney, Alex S F %A Morris, Andrew D %A Leese, Graham P %A Palmer, Colin N A %A Swaroop, Anand %A Taylor, Herman A %A Wilson, James G %A Penman, Alan %A Chen, Ching J %A Groop, Per-Henrik %A Saw, Seang-Mei %A Aung, Tin %A Klein, Barbara E %A Rotter, Jerome I %A Siscovick, David S %A Cotch, Mary Frances %A Klein, Ronald %A Daly, Mark J %A Wong, Tien Y %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K Diabetic Nephropathies %K Diabetic Retinopathy %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Iduronidase %K Odds Ratio %K P-Selectin %K Polymorphism, Single Nucleotide %K Risk Factors %X

PURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.

RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.

CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

%B Invest Ophthalmol Vis Sci %V 52 %P 7593-602 %8 2011 Sep 29 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21873659?dopt=Abstract %R 10.1167/iovs.11-7510 %0 Journal Article %J Ann Intern Med %D 2011 %T Circulating long-chain ω-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. %A Mozaffarian, Dariush %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Spiegelman, Donna %A Sacks, Frank M %A Rimm, Eric B %A Siscovick, David S %K Aged %K Biomarkers %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Fatty Acids, Omega-3 %K Fatty Acids, Unsaturated %K Feeding Behavior %K Heart Failure %K Humans %K Incidence %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %X

BACKGROUND: Few previous studies have evaluated associations between long-chain ω-3 fatty acids and incidence of congestive heart failure (CHF), and those that have are typically based on diet questionnaires and yield conflicting results. Circulating fatty acid concentrations provide objective biomarkers of exposure.

OBJECTIVE: To determine whether plasma phospholipid concentrations of long-chain ω-3 fatty acids, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), were associated with incident CHF.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PATIENTS: 2735 U.S. adults without prevalent heart disease who were enrolled in the Cardiovascular Health Study from 1992 to 2006.

MEASUREMENTS: Plasma phospholipid fatty acid concentrations and other cardiovascular risk factors were measured in 1992 by using standardized methods. Relationships with incident CHF (555 cases during 26 490 person-years, adjudicated by using medical records) were assessed by using Cox proportional hazards models.

RESULTS: After multivariate adjustment, plasma phospholipid EPA concentration was inversely associated with incident CHF; risk was approximately 50% lower in the highest versus the lowest quartile (hazard ratio [HR], 0.52 [95% CI, 0.38 to 0.72]; P for trend = 0.001). In similar analyses, trends toward lower risk were seen for DPA (HR, 0.76 [CI, 0.56 to 1.04]; P for trend = 0.057) and total long-chain ω-3 fatty acids (HR, 0.70 [CI, 0.49 to 0.99]; P for trend = 0.062) but not for DHA (HR, 0.84 [CI, 0.58 to 1.21]; P for trend = 0.38). In analyses censored to the middle of follow-up (7 years) to minimize exposure misclassification over time, multivariate-adjusted HRs were 0.48 for EPA (CI, 0.32 to 0.71; P for trend = 0.005), 0.61 for DPA (CI, 0.39 to 0.95; P for trend = 0.033), 0.64 for DHA (CI, 0.40 to 1.04; P for trend = 0.057), and 0.51 for total ω-3 fatty acids (CI, 0.32 to 0.80; P for trend = 0.003).

LIMITATIONS: Temporal changes in fatty acid concentrations over time may have caused underestimation of associations. Unmeasured or imperfectly measured covariates may have caused residual confounding.

CONCLUSION: Circulating individual and total ω-3 fatty acid concentrations are associated with lower incidence of CHF in older adults.

PRIMARY FUNDING SOURCE: National Institutes of Health.

%B Ann Intern Med %V 155 %P 160-70 %8 2011 Aug 02 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21810709?dopt=Abstract %R 10.7326/0003-4819-155-3-201108020-00006 %0 Journal Article %J J Am Soc Nephrol %D 2011 %T CUBN is a gene locus for albuminuria. %A Böger, Carsten A %A Chen, Ming-Huei %A Tin, Adrienne %A Olden, Matthias %A Köttgen, Anna %A de Boer, Ian H %A Fuchsberger, Christian %A O'Seaghdha, Conall M %A Pattaro, Cristian %A Teumer, Alexander %A Liu, Ching-Ti %A Glazer, Nicole L %A Li, Man %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Peralta, Carmen A %A Kutalik, Zoltán %A Luan, Jian'an %A Zhao, Jing Hua %A Hwang, Shih-Jen %A Akylbekova, Ermeg %A Kramer, Holly %A van der Harst, Pim %A Smith, Albert V %A Lohman, Kurt %A de Andrade, Mariza %A Hayward, Caroline %A Kollerits, Barbara %A Tönjes, Anke %A Aspelund, Thor %A Ingelsson, Erik %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Shuldiner, Alan R %A Mitchell, Braxton D %A Arking, Dan E %A Franceschini, Nora %A Boerwinkle, Eric %A Egan, Josephine %A Hernandez, Dena %A Reilly, Muredach %A Townsend, Raymond R %A Lumley, Thomas %A Siscovick, David S %A Psaty, Bruce M %A Kestenbaum, Bryan %A Haritunians, Talin %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Mooser, Vincent %A Waterworth, Dawn %A Johnson, Andrew D %A Florez, Jose C %A Meigs, James B %A Lu, Xiaoning %A Turner, Stephen T %A Atkinson, Elizabeth J %A Leak, Tennille S %A Aasarød, Knut %A Skorpen, Frank %A Syvänen, Ann-Christine %A Illig, Thomas %A Baumert, Jens %A Koenig, Wolfgang %A Krämer, Bernhard K %A Devuyst, Olivier %A Mychaleckyj, Josyf C %A Minelli, Cosetta %A Bakker, Stephan J L %A Kedenko, Lyudmyla %A Paulweber, Bernhard %A Coassin, Stefan %A Endlich, Karlhans %A Kroemer, Heyo K %A Biffar, Reiner %A Stracke, Sylvia %A Völzke, Henry %A Stumvoll, Michael %A Mägi, Reedik %A Campbell, Harry %A Vitart, Veronique %A Hastie, Nicholas D %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Polasek, Ozren %A Curhan, Gary %A Kronenberg, Florian %A Prokopenko, Inga %A Rudan, Igor %A Arnlöv, Johan %A Hallan, Stein %A Navis, Gerjan %A Parsa, Afshin %A Ferrucci, Luigi %A Coresh, Josef %A Shlipak, Michael G %A Bull, Shelley B %A Paterson, Nicholas J %A Wichmann, H-Erich %A Wareham, Nicholas J %A Loos, Ruth J F %A Rotter, Jerome I %A Pramstaller, Peter P %A Cupples, L Adrienne %A Beckmann, Jacques S %A Yang, Qiong %A Heid, Iris M %A Rettig, Rainer %A Dreisbach, Albert W %A Bochud, Murielle %A Fox, Caroline S %A Kao, W H L %K African Continental Ancestry Group %K Albuminuria %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Humans %K Mutation, Missense %K Receptors, Cell Surface %X

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.

%B J Am Soc Nephrol %V 22 %P 555-70 %8 2011 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract %R 10.1681/ASN.2010060598 %0 Journal Article %J PLoS Genet %D 2011 %T Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. %A Pasaniuc, Bogdan %A Zaitlen, Noah %A Lettre, Guillaume %A Chen, Gary K %A Tandon, Arti %A Kao, W H Linda %A Ruczinski, Ingo %A Fornage, Myriam %A Siscovick, David S %A Zhu, Xiaofeng %A Larkin, Emma %A Lange, Leslie A %A Cupples, L Adrienne %A Yang, Qiong %A Akylbekova, Ermeg L %A Musani, Solomon K %A Divers, Jasmin %A Mychaleckyj, Joe %A Li, Mingyao %A Papanicolaou, George J %A Millikan, Robert C %A Ambrosone, Christine B %A John, Esther M %A Bernstein, Leslie %A Zheng, Wei %A Hu, Jennifer J %A Ziegler, Regina G %A Nyante, Sarah J %A Bandera, Elisa V %A Ingles, Sue A %A Press, Michael F %A Chanock, Stephen J %A Deming, Sandra L %A Rodriguez-Gil, Jorge L %A Palmer, Cameron D %A Buxbaum, Sarah %A Ekunwe, Lynette %A Hirschhorn, Joel N %A Henderson, Brian E %A Myers, Simon %A Haiman, Christopher A %A Reich, David %A Patterson, Nick %A Wilson, James G %A Price, Alkes L %K African Americans %K Algorithms %K Breast Neoplasms %K Chromosome Mapping %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Female %K Gene Frequency %K Genetic Variation %K Genetics, Population %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Male %K Odds Ratio %K Phenotype %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Receptor, Fibroblast Growth Factor, Type 2 %K Software %X

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

%B PLoS Genet %V 7 %P e1001371 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21541012?dopt=Abstract %R 10.1371/journal.pgen.1001371 %0 Journal Article %J Stroke %D 2011 %T Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults. %A Thacker, Evan L %A Psaty, Bruce M %A McKnight, Barbara %A Heckbert, Susan R %A Longstreth, W T %A Mukamal, Kenneth J %A Meigs, James B %A de Boer, Ian H %A Boyko, Edward J %A Carnethon, Mercedes R %A Kizer, Jorge R %A Tracy, Russell P %A Smith, Nicholas L %A Siscovick, David S %K Aged %K Aged, 80 and over %K Blood Glucose %K Body Mass Index %K Brain Ischemia %K Fasting %K Female %K Humans %K Incidence %K Insulin Resistance %K Male %K Risk %K Stroke %X

BACKGROUND AND PURPOSE: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance.

RESULTS: Analyses included 3442 participants (42% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95% CI, 0.84-1.46).

CONCLUSIONS: In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.

%B Stroke %V 42 %P 3347-51 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21998054?dopt=Abstract %R 10.1161/STROKEAHA.111.620773 %0 Journal Article %J Am J Clin Nutr %D 2011 %T Fatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study. %A Wu, Jason H Y %A Lemaitre, Rozenn N %A Imamura, Fumiaki %A King, Irena B %A Song, Xiaoling %A Spiegelman, Donna %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Cohort Studies %K Coronary Disease %K Death, Sudden, Cardiac %K Diet %K Fatty Acids %K Female %K Humans %K Lipogenesis %K Male %K Phospholipids %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %X

BACKGROUND: De novo lipogenesis (DNL) is an endogenous pathway whereby carbohydrates and proteins are converted to fatty acids. DNL could affect coronary heart disease (CHD) or sudden cardiac arrest (SCA) via generation of specific fatty acids. Whether these fatty acids are prospectively associated with SCA or other CHD events is unknown.

OBJECTIVE: The objective was to investigate the relations of 4 fatty acids in the DNL pathway-palmitic acid (16:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and cis-vaccenic acid (18:1n-7)-with incident CHD, including fatal CHD, nonfatal myocardial infarction (NFMI), and SCA.

DESIGN: A community-based prospective study was conducted in 2890 men and women aged ≥65 y, who were free of known CHD at baseline and who were followed from 1992 to 2006. Cardiovascular disease risk factors and plasma phospholipid fatty acids were measured at baseline by using standardized methods. Incident CHD was ascertained prospectively and was centrally adjudicated by using medical records. Risk was assessed by using multivariable-adjusted Cox proportional hazards.

RESULTS: During 29,835 person-years of follow-up, 631 CHD and 71 SCA events occurred. Both 18:1n-7 and 16:1n-9 were associated with a higher risk of SCA [multivariable-adjusted hazard ratio (95% CI) for the interquintile range: 7.63 (2.58, 22.6) for 18:1n-7 and 2.30 (1.16, 4.55) for 16:1n-9] but not of total CHD, fatal CHD, or NFMI. In secondary analyses censored to mid-follow-up (7 y) to minimize the effects of changes in concentrations over time, 16:1n-9 was also associated with a significantly higher risk of total CHD (2.11; 1.76, 2.54), including a higher risk of CHD death, NFMI, and SCA; 16:0 and 16:1n-7 were not associated with clinical CHD outcomes.

CONCLUSION: Higher plasma phospholipid 18:1n-7 and 16:1n-9 concentrations were prospectively associated with an elevated risk of SCA but not of other CHD events, except in secondary analyses.

%B Am J Clin Nutr %V 94 %P 431-8 %8 2011 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21697077?dopt=Abstract %R 10.3945/ajcn.111.012054 %0 Journal Article %J PLoS Genet %D 2011 %T Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. %A Lemaitre, Rozenn N %A Tanaka, Toshiko %A Tang, Weihong %A Manichaikul, Ani %A Foy, Millennia %A Kabagambe, Edmond K %A Nettleton, Jennifer A %A King, Irena B %A Weng, Lu-Chen %A Bhattacharya, Sayanti %A Bandinelli, Stefania %A Bis, Joshua C %A Rich, Stephen S %A Jacobs, David R %A Cherubini, Antonio %A McKnight, Barbara %A Liang, Shuang %A Gu, Xiangjun %A Rice, Kenneth %A Laurie, Cathy C %A Lumley, Thomas %A Browning, Brian L %A Psaty, Bruce M %A Chen, Yii-der I %A Friedlander, Yechiel %A Djoussé, Luc %A Wu, Jason H Y %A Siscovick, David S %A Uitterlinden, André G %A Arnett, Donna K %A Ferrucci, Luigi %A Fornage, Myriam %A Tsai, Michael Y %A Mozaffarian, Dariush %A Steffen, Lyn M %K Alleles %K Continental Population Groups %K Fatty Acids, Omega-3 %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %X

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

%B PLoS Genet %V 7 %P e1002193 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21829377?dopt=Abstract %R 10.1371/journal.pgen.1002193 %0 Journal Article %J PLoS Genet %D 2011 %T Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. %A Arking, Dan E %A Junttila, M Juhani %A Goyette, Philippe %A Huertas-Vazquez, Adriana %A Eijgelsheim, Mark %A Blom, Marieke T %A Newton-Cheh, Christopher %A Reinier, Kyndaron %A Teodorescu, Carmen %A Uy-Evanado, Audrey %A Carter-Monroe, Naima %A Kaikkonen, Kari S %A Kortelainen, Marja-Leena %A Boucher, Gabrielle %A Lagacé, Caroline %A Moes, Anna %A Zhao, XiaoQing %A Kolodgie, Frank %A Rivadeneira, Fernando %A Hofman, Albert %A Witteman, Jacqueline C M %A Uitterlinden, André G %A Marsman, Roos F %A Pazoki, Raha %A Bardai, Abdennasser %A Koster, Rudolph W %A Dehghan, Abbas %A Hwang, Shih-Jen %A Bhatnagar, Pallav %A Post, Wendy %A Hilton, Gina %A Prineas, Ronald J %A Li, Man %A Köttgen, Anna %A Ehret, Georg %A Boerwinkle, Eric %A Coresh, Josef %A Kao, W H Linda %A Psaty, Bruce M %A Tomaselli, Gordon F %A Sotoodehnia, Nona %A Siscovick, David S %A Burke, Greg L %A Marbán, Eduardo %A Spooner, Peter M %A Cupples, L Adrienne %A Jui, Jonathan %A Gunson, Karen %A Kesaniemi, Y Antero %A Wilde, Arthur A M %A Tardif, Jean-Claude %A O'Donnell, Christopher J %A Bezzina, Connie R %A Virmani, Renu %A Stricker, Bruno H C H %A Tan, Hanno L %A Albert, Christine M %A Chakravarti, Aravinda %A Rioux, John D %A Huikuri, Heikki V %A Chugh, Sumeet S %K Adult %K Aged %K Alleles %K Chromosomes, Human, Pair 2 %K Death, Sudden, Cardiac %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Contraction %K Polymorphism, Single Nucleotide %X

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).

%B PLoS Genet %V 7 %P e1002158 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738491?dopt=Abstract %R 10.1371/journal.pgen.1002158 %0 Journal Article %J Am J Epidemiol %D 2011 %T Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women. %A Kizer, Jorge R %A Biggs, Mary L %A Ix, Joachim H %A Mukamal, Kenneth J %A Zieman, Susan J %A de Boer, Ian H %A Mozaffarian, Dariush %A Barzilay, Joshua I %A Strotmeyer, Elsa S %A Luchsinger, José A %A Elkind, Mitchell S V %A Longstreth, W T %A Kuller, Lewis H %A Siscovick, David S %K Adiposity %K Age Factors %K Aged %K Aged, 80 and over %K Brain Ischemia %K Coronary Disease %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Obesity %K Prevalence %K Retrospective Studies %K Risk Factors %K Sex Factors %K United States %X

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥ 30 kg/m²) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m² was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

%B Am J Epidemiol %V 173 %P 10-25 %8 2011 Jan 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21123850?dopt=Abstract %R 10.1093/aje/kwq311 %0 Journal Article %J Circulation %D 2011 %T Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. %A Dehghan, Abbas %A Dupuis, Josée %A Barbalic, Maja %A Bis, Joshua C %A Eiriksdottir, Gudny %A Lu, Chen %A Pellikka, Niina %A Wallaschofski, Henri %A Kettunen, Johannes %A Henneman, Peter %A Baumert, Jens %A Strachan, David P %A Fuchsberger, Christian %A Vitart, Veronique %A Wilson, James F %A Paré, Guillaume %A Naitza, Silvia %A Rudock, Megan E %A Surakka, Ida %A de Geus, Eco J C %A Alizadeh, Behrooz Z %A Guralnik, Jack %A Shuldiner, Alan %A Tanaka, Toshiko %A Zee, Robert Y L %A Schnabel, Renate B %A Nambi, Vijay %A Kavousi, Maryam %A Ripatti, Samuli %A Nauck, Matthias %A Smith, Nicholas L %A Smith, Albert V %A Sundvall, Jouko %A Scheet, Paul %A Liu, Yongmei %A Ruokonen, Aimo %A Rose, Lynda M %A Larson, Martin G %A Hoogeveen, Ron C %A Freimer, Nelson B %A Teumer, Alexander %A Tracy, Russell P %A Launer, Lenore J %A Buring, Julie E %A Yamamoto, Jennifer F %A Folsom, Aaron R %A Sijbrands, Eric J G %A Pankow, James %A Elliott, Paul %A Keaney, John F %A Sun, Wei %A Sarin, Antti-Pekka %A Fontes, João D %A Badola, Sunita %A Astor, Brad C %A Hofman, Albert %A Pouta, Anneli %A Werdan, Karl %A Greiser, Karin H %A Kuss, Oliver %A Meyer zu Schwabedissen, Henriette E %A Thiery, Joachim %A Jamshidi, Yalda %A Nolte, Ilja M %A Soranzo, Nicole %A Spector, Timothy D %A Völzke, Henry %A Parker, Alexander N %A Aspelund, Thor %A Bates, David %A Young, Lauren %A Tsui, Kim %A Siscovick, David S %A Guo, Xiuqing %A Rotter, Jerome I %A Uda, Manuela %A Schlessinger, David %A Rudan, Igor %A Hicks, Andrew A %A Penninx, Brenda W %A Thorand, Barbara %A Gieger, Christian %A Coresh, Joe %A Willemsen, Gonneke %A Harris, Tamara B %A Uitterlinden, André G %A Jarvelin, Marjo-Riitta %A Rice, Kenneth %A Radke, Dörte %A Salomaa, Veikko %A Willems van Dijk, Ko %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Ferrucci, Luigi %A Gibson, Quince D %A Bandinelli, Stefania %A Snieder, Harold %A Boomsma, Dorret I %A Xiao, Xiangjun %A Campbell, Harry %A Hayward, Caroline %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Peltonen, Leena %A Psaty, Bruce M %A Gudnason, Vilmundur %A Ridker, Paul M %A Homuth, Georg %A Koenig, Wolfgang %A Ballantyne, Christie M %A Witteman, Jacqueline C M %A Benjamin, Emelia J %A Perola, Markus %A Chasman, Daniel I %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Vasculitis %X

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

%B Circulation %V 123 %P 731-8 %8 2011 Feb 22 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.948570 %0 Journal Article %J J Clin Endocrinol Metab %D 2011 %T Mineral metabolism markers and the long-term risk of hip fracture: the cardiovascular health study. %A Robinson-Cohen, Cassianne %A Katz, Ronit %A Hoofnagle, Andrew N %A Cauley, Jane A %A Furberg, Curt D %A Robbins, John A %A Chen, Zhao %A Siscovick, David S %A de Boer, Ian H %A Kestenbaum, Bryan %K Aged %K Aged, 80 and over %K Alkaline Phosphatase %K Biomarkers %K Bone Density %K Female %K Hip Fractures %K Humans %K Male %K Parathyroid Hormone %K Risk %K Vitamin D %X

CONTEXT: Disturbances in mineral metabolism are associated with lower bone mineral density and fracture; however, previous human studies have assessed individual mineral metabolism markers in isolation.

OBJECTIVE: We assessed serum concentrations of 25-hydroxyvitamin D (25-OHD), PTH, and bone-specific alkaline phosphatase (BAP) concentrations individually, and in combination, in association with the long-term risk of hip fracture among a general population of older adults.

DESIGN AND SETTING: We studied 2294 participants from the Cardiovascular Health Study (mean age 74 yr) who were ambulatory and free of hip fracture and known cardiovascular disease at baseline. We used proportional hazards models to evaluate associations of baseline serum 25-OHD, PTH, and BAP concentrations with the time to first hospitalized hip fracture.

RESULTS: During a median of 13 yr of follow-up, 242 participants (10.6%) developed an incident hip fracture. Serum 25-OHD concentrations less than 15 ng/ml were associated with a 61% greater adjusted risk of fracture (95% confidence interval 12-132% greater). In contrast, neither serum PTH nor BAP concentrations were significantly associated with fracture risk. The association of 25-OHD deficiency with hip fracture was not significantly altered by either PTH or BAP concentrations.

CONCLUSIONS: Serum concentrations of 25-OHD, but not PTH or BAP, are associated with long-term hip fracture risk among ambulatory older adults. These data suggest that 25-OHD is the most relevant mineral metabolism marker of fracture risk among older people.

%B J Clin Endocrinol Metab %V 96 %P 2186-93 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21508146?dopt=Abstract %R 10.1210/jc.2010-2878 %0 Journal Article %J Heart Rhythm %D 2011 %T N-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study. %A Patton, Kristen K %A Sotoodehnia, Nona %A DeFilippi, Christopher %A Siscovick, David S %A Gottdiener, John S %A Kronmal, Richard A %K Age Distribution %K Aged %K Biomarkers %K Cardiovascular Diseases %K Cohort Studies %K Confidence Intervals %K Death, Sudden, Cardiac %K Female %K Humans %K Incidence %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Natriuretic Peptide, Brain %K Peptide Fragments %K Predictive Value of Tests %K Proportional Hazards Models %K Retrospective Studies %K Risk Assessment %K Sex Distribution %K Time Factors %K United States %X

BACKGROUND: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women.

OBJECTIVE: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.

METHODS: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP.

RESULTS: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95% confidence interval [1.6, 3.8]; P <.001).

CONCLUSION: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.

%B Heart Rhythm %V 8 %P 228-33 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21044699?dopt=Abstract %R 10.1016/j.hrthm.2010.10.038 %0 Journal Article %J Am J Clin Nutr %D 2011 %T Plasma omega-3 fatty acids and incident diabetes in older adults. %A Djoussé, Luc %A Biggs, Mary L %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Ix, Joachim H %A Mukamal, Kenneth J %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K alpha-Linolenic Acid %K Diabetes Mellitus %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Phospholipids %K Proportional Hazards Models %K Prospective Studies %X

BACKGROUND: Although long-chain omega-3 fatty acid (n-3 FA) consumption estimated via food-frequency questionnaires has been associated with a higher incidence of diabetes, limited prospective data on diabetes risk are available that use objective biomarkers of n-3 FAs.

OBJECTIVE: We sought to examine the relation between plasma phospholipid n-3 FAs and incident diabetes.

DESIGN: We prospectively analyzed data in 3088 older men and women (mean age: 75 y) from the Cardiovascular Health Study (1992-2007). Plasma phospholipid n-3 FAs were measured by using gas chromatography, and incident diabetes was ascertained by using information on hypoglycemic agents and serum glucose. We used Cox proportional hazards models to estimate multivariable-adjusted relative risks.

RESULTS: During a median follow-up of 10.6 y, 204 new cases of diabetes occurred. In a multivariable model that controlled for age, sex, race, clinic site, body mass index, alcohol intake, smoking, physical activity, LDL cholesterol, and linoleic acid, relative risks (95% CIs) for diabetes were 1.0 (reference), 0.96 (0.65, 1.43), 1.03 (0.69, 1.54), and 0.64 (0.41, 1.01) across consecutive quartiles of phospholipid eicosapentaenoic acid and docosahexaenoic acid (P for trend = 0.05). Corresponding relative risks (95% CIs) for phospholipid α-linolenic acid (ALA) were 1.0 (reference), 0.93 (0.65, 1.34), 0.99 (0.68, 1.44), and 0.57 (0.36, 0.90) (P for trend = 0.03).

CONCLUSIONS: With the use of objective biomarkers, long-chain n-3 FAs and ALA were not associated with a higher incidence of diabetes. Individuals with the highest concentrations of both types of FAs had lower risk of diabetes.

%B Am J Clin Nutr %V 94 %P 527-33 %8 2011 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21593500?dopt=Abstract %R 10.3945/ajcn.111.013334 %0 Journal Article %J Curr Gerontol Geriatr Res %D 2011 %T Potential explanatory factors for higher incident hip fracture risk in older diabetic adults. %A Strotmeyer, Elsa S %A Kamineni, Aruna %A Cauley, Jane A %A Robbins, John A %A Fried, Linda F %A Siscovick, David S %A Harris, Tamara B %A Newman, Anne B %X

Type 2 diabetes is associated with higher fracture risk. Diabetes-related conditions may account for this risk. Cardiovascular Health Study participants (N = 5641; 42.0% men; 15.5% black; 72.8±5.6 years) were followed 10.9 ± 4.6 years. Diabetes was defined as hypoglycemic medication use or fasting glucose (FG) ≥126 mg/dL. Peripheral artery disease (PAD) was defined as ankle-arm index <0.9. Incident hip fractures were from medical records. Crude hip fracture rates (/1000 person-years) were higher for diabetic vs. non-diabetic participants with BMI <25 (13.6, 95% CI: 8.9-20.2 versus 11.4, 95% CI: 10.1-12.9) and BMI ≥25 to <30 (8.3, 95% CI: 5.7-11.9 versus 6.6, 95% CI: 5.6-7.7), but similar for BMI ≥30. Adjusting for BMI, sex, race, and age, diabetes was related to fractures (HR = 1.34; 95% CI: 1.01-1.78). PAD (HR = 1.25 (95% CI: 0.92-1.57)) and longer walk time (HR = 1.07 (95% CI: 1.04-1.10)) modified the fracture risk in diabetes (HR = 1.17 (95% CI: 0.87-1.57)). Diabetes was associated with higher hip fracture risk after adjusting for BMI though this association was modified by diabetes-related conditions.

%B Curr Gerontol Geriatr Res %V 2011 %P 979270 %8 2011 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/21837239?dopt=Abstract %R 10.1155/2011/979270 %0 Journal Article %J Am J Epidemiol %D 2011 %T Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study. %A Shoben, Abigail B %A Kestenbaum, Bryan %A Levin, Gregory %A Hoofnagle, Andrew N %A Psaty, Bruce M %A Siscovick, David S %A de Boer, Ian H %K Aged %K Biomarkers %K Continental Population Groups %K Exercise %K Female %K Humans %K Male %K Residence Characteristics %K Seasons %K Sex Factors %K Vitamin D %X

Low circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992-1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.

%B Am J Epidemiol %V 174 %P 1363-72 %8 2011 Dec 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/22112344?dopt=Abstract %R 10.1093/aje/kwr258 %0 Journal Article %J Clin J Am Soc Nephrol %D 2011 %T Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. %A de Boer, Ian H %A Katz, Ronit %A Chonchol, Michel %A Ix, Joachim H %A Sarnak, Mark J %A Shlipak, Michael G %A Siscovick, David S %A Kestenbaum, Bryan %K Aged %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Diseases %K Male %K Prospective Studies %K Vitamin D %X

BACKGROUND AND OBJECTIVES: Mounting evidence suggests that 1,25-dihydroxyvitamin D prevents the progression of chronic kidney disease (CKD). It is not clear whether "nutritional" forms of vitamin D affect GFR.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested whether serum 25-hydroxyvitamin D concentration (25(OH)D), a measure of total vitamin D intake from cutaneous synthesis and dietary consumption, is associated with loss of estimated GFR among 1705 older adults with predominantly normal baseline kidney function participating in the Cardiovascular Health Study. Baseline 25(OH)D was measured by HPLC-tandem mass spectrometry. GFR was estimated at baseline and 4 years later using the CKD-EPI formula, with rapid GFR loss defined as 12 ml/min per 1.73 m(2) or more over 4 years.

RESULTS: Rapid GFR loss was observed for 207 participants (12%). Each 10 ng/ml lower 25(OH)D was associated with a 25% greater risk of rapid GFR loss (95% confidence interval [CI] 5%, 49%, P = 0.01), adjusting for potential confounding characteristics. Compared with 25(OH)D ≥30 ng/ml, 25(OH)D concentrations 15 to 29 ng/ml and <15 ng/ml were associated with 29% (95% CI -13%, 91%) and 68% (95% CI 1%, 177%) greater adjusted risks of rapid GFR loss, respectively. Magnitudes of association were largest among participants with diabetes.

RESULTS: were similar evaluating a composite outcome of rapid GFR loss, end stage renal disease, and death. Conclusions Insufficient 25(OH)D may be a modifiable risk factor for early GFR loss. We recommend clinical trials to determine whether vitamin D supplementation prevents the development and progression of CKD.

%B Clin J Am Soc Nephrol %V 6 %P 2141-9 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21836148?dopt=Abstract %R 10.2215/CJN.02640311 %0 Journal Article %J Diabetes %D 2011 %T Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. %A Kanoni, Stavroula %A Nettleton, Jennifer A %A Hivert, Marie-France %A Ye, Zheng %A van Rooij, Frank J A %A Shungin, Dmitry %A Sonestedt, Emily %A Ngwa, Julius S %A Wojczynski, Mary K %A Lemaitre, Rozenn N %A Gustafsson, Stefan %A Anderson, Jennifer S %A Tanaka, Toshiko %A Hindy, George %A Saylor, Georgia %A Renstrom, Frida %A Bennett, Amanda J %A van Duijn, Cornelia M %A Florez, Jose C %A Fox, Caroline S %A Hofman, Albert %A Hoogeveen, Ron C %A Houston, Denise K %A Hu, Frank B %A Jacques, Paul F %A Johansson, Ingegerd %A Lind, Lars %A Liu, Yongmei %A McKeown, Nicola %A Ordovas, Jose %A Pankow, James S %A Sijbrands, Eric J G %A Syvänen, Ann-Christine %A Uitterlinden, André G %A Yannakoulia, Mary %A Zillikens, M Carola %A Wareham, Nick J %A Prokopenko, Inga %A Bandinelli, Stefania %A Forouhi, Nita G %A Cupples, L Adrienne %A Loos, Ruth J %A Hallmans, Göran %A Dupuis, Josée %A Langenberg, Claudia %A Ferrucci, Luigi %A Kritchevsky, Stephen B %A McCarthy, Mark I %A Ingelsson, Erik %A Borecki, Ingrid B %A Witteman, Jacqueline C M %A Orho-Melander, Marju %A Siscovick, David S %A Meigs, James B %A Franks, Paul W %A Dedoussis, George V %K Blood Glucose %K Cation Transport Proteins %K Cohort Studies %K Humans %K Polymorphism, Single Nucleotide %K Zinc %K Zinc Transporter 8 %X

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

%B Diabetes %V 60 %P 2407-16 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21810599?dopt=Abstract %R 10.2337/db11-0176 %0 Journal Article %J J Am Coll Cardiol %D 2011 %T Vitamin D, parathyroid hormone, and cardiovascular events among older adults. %A Kestenbaum, Bryan %A Katz, Ronit %A de Boer, Ian %A Hoofnagle, Andy %A Sarnak, Mark J %A Shlipak, Michael G %A Jenny, Nancy S %A Siscovick, David S %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Cardiovascular Diseases %K Cohort Studies %K Female %K Follow-Up Studies %K Humans %K Male %K Parathyroid Hormone %K Prospective Studies %K Vitamin D %X

OBJECTIVES: The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study).

BACKGROUND: Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health.

METHODS: A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality.

RESULTS: There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval [CI]: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.

CONCLUSIONS: Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.

%B J Am Coll Cardiol %V 58 %P 1433-41 %8 2011 Sep 27 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/21939825?dopt=Abstract %R 10.1016/j.jacc.2011.03.069 %0 Journal Article %J Obesity (Silver Spring) %D 2012 %T Adiposity and incident heart failure in older adults: the cardiovascular health study. %A Djoussé, Luc %A Bartz, Traci M %A Ix, Joachim H %A Zieman, Susan J %A Delaney, Joseph A %A Mukamal, Kenneth J %A Gottdiener, John S %A Siscovick, David S %A Kizer, Jorge R %K Adiposity %K Aged %K Aging %K Body Fat Distribution %K Body Mass Index %K Female %K Heart Failure %K Humans %K Incidence %K Independent Living %K Male %K Obesity %K Predictive Value of Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Sex Factors %K United States %K Waist Circumference %X

While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident HF in older adults. We sought to examine the association between waist circumference (WC) and incident HF and assess whether sex modifies the relation between WC and HF. Prospective study using data on 4,861 participants of the Cardiovascular Health Study (1989-2007). HF was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio (HR). The mean age was 73.0 years for men and 72.3 years for women; 42.5% were men and 15.3% were African Americans. WC was positively associated with an increased risk of HF: each standard deviation of WC was associated with a 14% increased risk of HF (95% CI: 3%-26%) in a multivariable model. There was not a statistically significant sex-by-WC interaction (P = 0.081). BMI was positively associated with incident HF (HR: 1.22 (95% CI: 1.15-1.29) per standard deviation increase of BMI); however, this association was attenuated and became nonstatistically significant upon additional adjustment for WC (HR: 1.09 (95% CI: 0.99-1.21)). In conclusion, a higher WC is associated with an increased risk of HF independent of BMI in community-living older men and women.

%B Obesity (Silver Spring) %V 20 %P 1936-41 %8 2012 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22016094?dopt=Abstract %R 10.1038/oby.2011.320 %0 Journal Article %J Circulation %D 2012 %T Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. %A Ix, Joachim H %A Biggs, Mary L %A Mukamal, Kenneth J %A Kizer, Jorge R %A Zieman, Susan J %A Siscovick, David S %A Mozzaffarian, Dariush %A Jensen, Majken K %A Nelson, Lauren %A Ruderman, Neil %A Djoussé, Luc %K African Continental Ancestry Group %K Age Distribution %K Aged %K Aged, 80 and over %K alpha-2-HS-Glycoprotein %K Body Mass Index %K C-Reactive Protein %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Humans %K Incidence %K Life Style %K Lipids %K Male %K Pilot Projects %K Prevalence %K Proportional Hazards Models %K Residence Characteristics %K Risk Factors %K Sex Distribution %X

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.

%B Circulation %V 125 %P 2316-22 %8 2012 May 15 %G eng %N 19 %1 http://www.ncbi.nlm.nih.gov/pubmed/22511752?dopt=Abstract %R 10.1161/CIRCULATIONAHA.111.072751 %0 Journal Article %J Circulation %D 2012 %T Association of plasma phospholipid long-chain ω-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study. %A Wu, Jason H Y %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Sacks, Frank M %A Rimm, Eric B %A Heckbert, Susan R %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Atrial Fibrillation %K Biomarkers %K Dietary Fats %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Fatty Acids, Omega-3 %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Risk Factors %K Seafood %X

BACKGROUND: Experimental studies suggest that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) may reduce the risk of atrial fibrillation (AF). Prior studies evaluating fish or n-3 PUFA consumption from dietary questionnaires and incident AF have been conflicting. Circulating levels of n-3 PUFAs provide an objective measurement of exposure.

METHODS AND RESULTS: Among 3326 US men and women ≥65 years of age and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were measured at baseline by use of standardized methods. Incident AF (789 cases) was identified prospectively from hospital discharge records and study visit ECGs during 31 169 person-years of follow-up (1992-2006). In multivariable Cox models adjusted for other risk factors, the relative risk in the top versus lowest quartile of total n-3 PUFAs (eicosapentaenoic acid+docosapentaenoic acid+docosahexaenoic acid) levels was 0.71 (95% confidence interval, 0.57-0.89; P for trend=0.004) and of DHA levels was 0.77 (95% confidence interval, 0.62-0.96; P for trend=0.01). Eicosapentaenoic acid and docosapentaenoic acid levels were not significantly associated with incident AF. Evaluated nonparametrically, both total n-3 PUFAs and docosahexaenoic acid showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results.

CONCLUSIONS: In older adults, higher circulating total long-chain n-3 PUFA and docosahexaenoic acid levels were associated with lower risk of incident AF. These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for the primary prevention of AF.

%B Circulation %V 125 %P 1084-93 %8 2012 Mar 06 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22282329?dopt=Abstract %R 10.1161/CIRCULATIONAHA.111.062653 %0 Journal Article %J Circulation %D 2012 %T Associations of total and high-molecular-weight adiponectin with all-cause and cardiovascular mortality in older persons: the Cardiovascular Health Study. %A Kizer, Jorge R %A Benkeser, David %A Arnold, Alice M %A Mukamal, Kenneth J %A Ix, Joachim H %A Zieman, Susan J %A Siscovick, David S %A Tracy, Russell P %A Mantzoros, Christos S %A deFilippi, Christopher R %A Newman, Anne B %A Djoussé, Luc %K Adiponectin %K Aged %K Aged, 80 and over %K Body Mass Index %K Cardiovascular Diseases %K Female %K Health Surveys %K Humans %K Male %K Molecular Weight %X

BACKGROUND: Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk).

METHODS AND RESULTS: In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality.

CONCLUSIONS: Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults.

%B Circulation %V 126 %P 2951-61 %8 2012 Dec 18 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/23159554?dopt=Abstract %R 10.1161/CIRCULATIONAHA.112.135202 %0 Journal Article %J Clin J Am Soc Nephrol %D 2012 %T Chronic kidney disease, insulin resistance, and incident diabetes in older adults. %A Pham, Hien %A Robinson-Cohen, Cassianne %A Biggs, Mary L %A Ix, Joachim H %A Mukamal, Kenneth J %A Fried, Linda F %A Kestenbaum, Bryan %A Siscovick, David S %A de Boer, Ian H %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Chronic Disease %K Creatinine %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Glucose Tolerance Test %K Health Surveys %K Humans %K Hypoglycemic Agents %K Incidence %K Insulin %K Insulin Resistance %K Insulin-Secreting Cells %K Kidney %K Kidney Diseases %K Linear Models %K Male %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K United States %X

BACKGROUND AND OBJECTIVES: Insulin resistance is a complication of advanced CKD. Insulin resistance is less well characterized in earlier stages of CKD. The response of the pancreatic β cell, effects on glucose tolerance, and risk of diabetes are not clear.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Health Study included 4680 adults without baseline diabetes. The Chronic Kidney Disease Epidemiology Collaboration creatinine equation was used to obtain the estimated GFR (eGFR). Insulin resistance was evaluated as fasting insulin concentration. The insulin sensitivity index, β cell function, and glucose tolerance were assessed by oral glucose tolerance testing. Incident diabetes was defined as fasting glucose ≥126 mg/dl, nonfasting glucose ≥200 mg/dl, or use of glucose-lowering medications.

RESULTS: Mean age was 72.5 years (range, 65-98 years). Mean eGFR was 72.2 (SD 17.1) ml/min per 1.73 m(2). After adjustment, each 10 ml/min per 1.73 m(2) lower eGFR was associated with a 2.2% higher fasting insulin concentration (95% confidence interval [CI], 1.4%, 2.9%; P<0.001) and a 1.1% lower insulin sensitivity index (95% CI, 0.03%, 2.2%; P=0.04). Surprisingly, eGFR was associated with an augmented β cell function index (P<0.001), lower 2-hour glucose concentration (P=0.002), and decreased risk of glucose intolerance (P=0.006). Over a median 12 years' follow-up, 437 participants (9.3%) developed diabetes. eGFR was not associated with the risk of incident diabetes.

CONCLUSIONS: Among older adults, lower eGFR was associated with insulin resistance. However, with lower eGFR, β cell function was appropriately augmented and risks of impaired glucose tolerance and incident diabetes were not increased.

%B Clin J Am Soc Nephrol %V 7 %P 588-94 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22383749?dopt=Abstract %R 10.2215/CJN.11861111 %0 Journal Article %J Am J Clin Nutr %D 2012 %T Circulating and dietary α-linolenic acid and incidence of congestive heart failure in older adults: the Cardiovascular Health Study. %A Lemaitre, Rozenn N %A Sitlani, Colleen %A Song, Xiaoling %A King, Irena B %A McKnight, Barbara %A Spiegelman, Donna %A Sacks, Frank M %A Djoussé, Luc %A Rimm, Eric B %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Alcohol Drinking %K alpha-Linolenic Acid %K Biomarkers %K Body Mass Index %K Cardiovascular Diseases %K Diet %K Fatty Acid Desaturases %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Polymorphism, Single Nucleotide %K Prevalence %K Prospective Studies %K Risk Factors %K Smoking %K Surveys and Questionnaires %K United States %X

BACKGROUND: Few studies have evaluated the association between the n-3 fatty acid α-linolenic acid (ALA) and the incidence of congestive heart failure (CHF).

OBJECTIVE: We investigated whether plasma phospholipid concentrations and estimated dietary consumption of ALA are associated with incident CHF.

DESIGN: We used data from the Cardiovascular Health Study, a prospective cohort study of cardiovascular diseases among adults aged ≥65 y, from 4 US communities. A total of 2957 participants free of prevalent heart disease and with available fatty acid measurements were included in biomarker analyses (30,722 person-years and 686 incident CHF events). A total of 4432 participants free of prevalent heart disease were included in dietary analyses (52,609 person-years and 1072 events). We investigated the association of ALA with incident CHF by using Cox regression.

RESULTS: After adjustment for age, sex, race, education, smoking status, BMI, waist circumference, and alcohol consumption, plasma phospholipid ALA was not associated with incident CHF (HR for the highest compared with the lowest quartile: 0.97; 95% CI: 0.79, 1.21; P-trend = 0.85). Likewise, dietary ALA was not associated with incident CHF (adjusted HR for the highest compared with the lowest quartile: 0.96; 95% CI: 0.82, 1.20; P-trend = 0.97). We observed no association of biomarker or dietary ALA with nonvalvular CHF subtype. We also found little evidence of an association between ALA and CHF in subgroups based on age, sex, diabetes, fish consumption, BMI, or FADS2 genotype (rs1535).

CONCLUSION: ALA intake is not associated with incident CHF in older adults. This trial was registered at clinicaltrials.gov as NCT00005133.

%B Am J Clin Nutr %V 96 %P 269-74 %8 2012 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22743310?dopt=Abstract %R 10.3945/ajcn.112.037960 %0 Journal Article %J J Am Coll Cardiol %D 2012 %T Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). %A Ix, Joachim H %A Katz, Ronit %A Kestenbaum, Bryan R %A de Boer, Ian H %A Chonchol, Michel %A Mukamal, Kenneth J %A Rifkin, Dena %A Siscovick, David S %A Sarnak, Mark J %A Shlipak, Michael G %K Aged %K Aged, 80 and over %K Biomarkers %K Female %K Fibroblast Growth Factors %K Heart Failure %K Humans %K Kidney Function Tests %K Male %K Mortality %K Renal Insufficiency, Chronic %K United States %X

OBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting.

BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown.

METHODS: Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.

RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45).

CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.

%B J Am Coll Cardiol %V 60 %P 200-7 %8 2012 Jul 17 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22703926?dopt=Abstract %R 10.1016/j.jacc.2012.03.040 %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide association and functional follow-up reveals new loci for kidney function. %A Pattaro, Cristian %A Köttgen, Anna %A Teumer, Alexander %A Garnaas, Maija %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Taliun, Daniel %A Li, Man %A Gao, Xiaoyi %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A O'Seaghdha, Conall M %A Glazer, Nicole %A Isaacs, Aaron %A Liu, Ching-Ti %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Johnson, Andrew D %A Gierman, Hinco J %A Feitosa, Mary %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Chouraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Cavalieri, Margherita %A Rao, Madhumathi %A Hu, Frank B %A Demirkan, Ayse %A Oostra, Ben A %A de Andrade, Mariza %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Kolcic, Ivana %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Endlich, Karlhans %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Ketkar, Shamika %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Giulianini, Franco %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Metzger, Marie %A Mitchell, Paul %A Ciullo, Marina %A Kim, Stuart K %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Siscovick, David S %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline C M %A Hayward, Caroline %A Ridker, Paul %A Parsa, Afshin %A Bochud, Murielle %A Heid, Iris M %A Goessling, Wolfram %A Chasman, Daniel I %A Kao, W H Linda %A Fox, Caroline S %K African Americans %K Aged %K Animals %K Caspase 9 %K Cyclin-Dependent Kinases %K DEAD-box RNA Helicases %K DNA Helicases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Knockdown Techniques %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Phosphoric Diester Hydrolases %K Zebrafish %X

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.

%B PLoS Genet %V 8 %P e1002584 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract %R 10.1371/journal.pgen.1002584 %0 Journal Article %J PLoS One %D 2012 %T Hemoglobin A1c and arterial and ventricular stiffness in older adults. %A Zieman, Susan J %A Kamineni, Aruna %A Ix, Joachim H %A Barzilay, Joshua %A Djoussé, Luc %A Kizer, Jorge R %A Biggs, Mary L %A de Boer, Ian H %A Chonchol, Michel %A Gottdiener, John S %A Selvin, Elizabeth %A Newman, Anne B %A Kuller, Lewis H %A Siscovick, David S %A Mukamal, Kenneth J %K Adult %K African Continental Ancestry Group %K Aged %K Ankle Brachial Index %K Arteries %K Blood Glucose %K Blood Pressure %K Body Mass Index %K Cross-Sectional Studies %K Fasting %K Female %K Genetic Association Studies %K Glycated Hemoglobin A %K Glycation End Products, Advanced %K Heart Ventricles %K Humans %K Male %K Middle Aged %K Ultrasonography %K Vascular Stiffness %X

OBJECTIVE: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA(1c), an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.

RESEARCH DESIGN & METHODS: Baseline HbA(1c) was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥ 65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA(1c) and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.

RESULTS: HbA(1c) was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA(1c) was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.

CONCLUSIONS: In this sample of older adults without diabetes, HbA(1c) was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.

%B PLoS One %V 7 %P e47941 %8 2012 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/23118911?dopt=Abstract %R 10.1371/journal.pone.0047941 %0 Journal Article %J Vasc Med %D 2012 %T Insulin resistance and incident peripheral artery disease in the Cardiovascular Health Study. %A Britton, Kathryn A %A Mukamal, Kenneth J %A Ix, Joachim H %A Siscovick, David S %A Newman, Anne B %A de Boer, Ian H %A Thacker, Evan L %A Biggs, Mary L %A Gaziano, J Michael %A Djoussé, Luc %K Aged %K Ankle Brachial Index %K Biomarkers %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Diabetic Angiopathies %K Fasting %K Female %K Health Surveys %K Humans %K Incidence %K Insulin %K Insulin Resistance %K Logistic Models %K Longitudinal Studies %K Male %K Odds Ratio %K Peripheral Arterial Disease %K Predictive Value of Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

Type 2 diabetes is a risk factor for peripheral artery disease (PAD), and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by two methods. PAD was first defined as the development of an abnormal ankle-brachial index (ABI) (dichotomous outcome) after 6 years of follow-up. PAD was alternatively defined as the development of clinical PAD (time-to-event analysis). The study samples included adults over the age of 65 years who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, body mass index (BMI), smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n = 2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (odds ratio = 1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval [CI] 1.20-2.71). In the clinical PAD analysis (n = 4208), we found a similar relation (hazard ratio = 2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% CI 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.

%B Vasc Med %V 17 %P 85-93 %8 2012 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22402937?dopt=Abstract %R 10.1177/1358863X11436195 %0 Journal Article %J Diabetes Care %D 2012 %T Insulin resistance, cystatin C, and mortality among older adults. %A de Boer, Ian H %A Katz, Ronit %A Chonchol, Michel B %A Fried, Linda F %A Ix, Joachim H %A Kestenbaum, Bryan %A Mukamal, Kenneth J %A Peralta, Carmen A %A Siscovick, David S %K Aged %K Aged, 80 and over %K Blood Glucose %K Blood Pressure %K C-Reactive Protein %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Cystatin C %K Fasting %K Female %K Glomerular Filtration Rate %K Humans %K Insulin Resistance %K Life Style %K Male %K Mortality %K Predictive Value of Tests %K Proportional Hazards Models %K Renal Insufficiency %K Risk Factors %K Triglycerides %K Waist Circumference %X

OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.

RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥ 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).

RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6-41) and 11% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4-43) and 4% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.

CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.

%B Diabetes Care %V 35 %P 1355-60 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22432118?dopt=Abstract %R 10.2337/dc11-1657 %0 Journal Article %J Circ Arrhythm Electrophysiol %D 2012 %T Nonesterified fatty acids and risk of sudden cardiac death in older adults. %A Djoussé, Luc %A Biggs, Mary L %A Ix, Joachim H %A Kizer, Jorge R %A Lemaitre, Rozenn N %A Sotoodehnia, Nona %A Zieman, Susan J %A Mozaffarian, Dariush %A Tracy, Russell P %A Mukamal, Kenneth J %A Siscovick, David S %K Aged %K Aged, 80 and over %K Biomarkers %K Death, Sudden, Cardiac %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Prospective Studies %K Retrospective Studies %K Risk Factors %X

BACKGROUND: Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.

METHODS AND RESULTS: Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.

CONCLUSIONS: Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.

%B Circ Arrhythm Electrophysiol %V 5 %P 273-8 %8 2012 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22281952?dopt=Abstract %R 10.1161/CIRCEP.111.967661 %0 Journal Article %J Am J Clin Nutr %D 2012 %T Novel circulating fatty acid patterns and risk of cardiovascular disease: the Cardiovascular Health Study. %A Imamura, Fumiaki %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Lichtenstein, Alice H %A Matthan, Nirupa R %A Herrington, David M %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Biomarkers %K Cardiovascular Diseases %K Cohort Studies %K Coronary Artery Disease %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Myocardial Ischemia %K Principal Component Analysis %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Stroke %K Trans Fatty Acids %K United States %X

BACKGROUND: Complex interplays of diet and metabolism influence circulating fatty acids (FAs), possibly constituting FA patterns related to cardiovascular disease (CVD) risk.

OBJECTIVES: We aimed to derive FA patterns from circulating FAs, relate the patterns to CVD incidence, and extend the derived patterns to atherosclerosis progression in another independent cohort.

DESIGN: We used principal component analysis (PCA) to derive FA patterns from 38 plasma phospholipid FAs in 2972 older adults in the Cardiovascular Health Study (CHS). Identified patterns were evaluated for prospective associations with 14-y incidence of CVD [ischemic heart disease (IHD) or stroke]. In another independent cohort of postmenopausal women with IHD, we evaluated associations of the CHS-derived patterns with 3.2-y progression of angiographically defined coronary atherosclerosis.

RESULTS: Three distinct patterns were identified, characterized by higher proportions of trans FAs, de novo lipogenesis (DNL) FAs, and long-chain MUFAs (LCMUFAs). During 32,265 person-years, 780 incident CVD events occurred. The trans FA pattern was associated with higher CVD risk (multivariable-adjusted HR for the highest compared with the lowest quintiles = 1.58; 95% CI: 1.17, 2.12; P-trend = 0.006), primarily attributable to higher risk of stroke (HR: 2.46; 95% CI: 1.54, 3.92; P-trend = 0.005). The DNL and LCMUFA patterns were not associated with CVD incidence or with IHD or stroke (P-trend > 0.11 each). In the second cohort, the trans FA pattern, but not the other 2 patterns, was positively associated with progression of coronary atherosclerosis (P-trend < 0.05).

CONCLUSIONS: PCA appears to provide informative circulating FA patterns. A pattern driven mainly by trans FA levels related to greater CVD risk in older adults and coronary atherosclerosis progression in women with IHD.

%B Am J Clin Nutr %V 96 %P 1252-61 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23097270?dopt=Abstract %R 10.3945/ajcn.112.039990 %0 Journal Article %J PLoS Genet %D 2012 %T Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. %A Dastani, Zari %A Hivert, Marie-France %A Timpson, Nicholas %A Perry, John R B %A Yuan, Xin %A Scott, Robert A %A Henneman, Peter %A Heid, Iris M %A Kizer, Jorge R %A Lyytikäinen, Leo-Pekka %A Fuchsberger, Christian %A Tanaka, Toshiko %A Morris, Andrew P %A Small, Kerrin %A Isaacs, Aaron %A Beekman, Marian %A Coassin, Stefan %A Lohman, Kurt %A Qi, Lu %A Kanoni, Stavroula %A Pankow, James S %A Uh, Hae-Won %A Wu, Ying %A Bidulescu, Aurelian %A Rasmussen-Torvik, Laura J %A Greenwood, Celia M T %A Ladouceur, Martin %A Grimsby, Jonna %A Manning, Alisa K %A Liu, Ching-Ti %A Kooner, Jaspal %A Mooser, Vincent E %A Vollenweider, Peter %A Kapur, Karen A %A Chambers, John %A Wareham, Nicholas J %A Langenberg, Claudia %A Frants, Rune %A Willems-Vandijk, Ko %A Oostra, Ben A %A Willems, Sara M %A Lamina, Claudia %A Winkler, Thomas W %A Psaty, Bruce M %A Tracy, Russell P %A Brody, Jennifer %A Chen, Ida %A Viikari, Jorma %A Kähönen, Mika %A Pramstaller, Peter P %A Evans, David M %A St Pourcain, Beate %A Sattar, Naveed %A Wood, Andrew R %A Bandinelli, Stefania %A Carlson, Olga D %A Egan, Josephine M %A Böhringer, Stefan %A van Heemst, Diana %A Kedenko, Lyudmyla %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Loo, Britt-Marie %A Harris, Tamara %A Garcia, Melissa %A Kanaya, Alka %A Haun, Margot %A Klopp, Norman %A Wichmann, H-Erich %A Deloukas, Panos %A Katsareli, Efi %A Couper, David J %A Duncan, Bruce B %A Kloppenburg, Margreet %A Adair, Linda S %A Borja, Judith B %A Wilson, James G %A Musani, Solomon %A Guo, Xiuqing %A Johnson, Toby %A Semple, Robert %A Teslovich, Tanya M %A Allison, Matthew A %A Redline, Susan %A Buxbaum, Sarah G %A Mohlke, Karen L %A Meulenbelt, Ingrid %A Ballantyne, Christie M %A Dedoussis, George V %A Hu, Frank B %A Liu, Yongmei %A Paulweber, Bernhard %A Spector, Timothy D %A Slagboom, P Eline %A Ferrucci, Luigi %A Jula, Antti %A Perola, Markus %A Raitakari, Olli %A Florez, Jose C %A Salomaa, Veikko %A Eriksson, Johan G %A Frayling, Timothy M %A Hicks, Andrew A %A Lehtimäki, Terho %A Smith, George Davey %A Siscovick, David S %A Kronenberg, Florian %A van Duijn, Cornelia %A Loos, Ruth J F %A Waterworth, Dawn M %A Meigs, James B %A Dupuis, Josée %A Richards, J Brent %A Voight, Benjamin F %A Scott, Laura J %A Steinthorsdottir, Valgerdur %A Dina, Christian %A Welch, Ryan P %A Zeggini, Eleftheria %A Huth, Cornelia %A Aulchenko, Yurii S %A Thorleifsson, Gudmar %A McCulloch, Laura J %A Ferreira, Teresa %A Grallert, Harald %A Amin, Najaf %A Wu, Guanming %A Willer, Cristen J %A Raychaudhuri, Soumya %A McCarroll, Steve A %A Hofmann, Oliver M %A Segrè, Ayellet V %A van Hoek, Mandy %A Navarro, Pau %A Ardlie, Kristin %A Balkau, Beverley %A Benediktsson, Rafn %A Bennett, Amanda J %A Blagieva, Roza %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Boström, Kristina Bengtsson %A Bravenboer, Bert %A Bumpstead, Suzannah %A Burtt, Noel P %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn %A Crawford, Gabe %A Doney, Alex S F %A Elliott, Katherine S %A Elliott, Amanda L %A Erdos, Michael R %A Fox, Caroline S %A Franklin, Christopher S %A Ganser, Martha %A Gieger, Christian %A Grarup, Niels %A Green, Todd %A Griffin, Simon %A Groves, Christopher J %A Guiducci, Candace %A Hadjadj, Samy %A Hassanali, Neelam %A Herder, Christian %A Isomaa, Bo %A Jackson, Anne U %A Johnson, Paul R V %A Jørgensen, Torben %A Kao, Wen H L %A Kong, Augustine %A Kraft, Peter %A Kuusisto, Johanna %A Lauritzen, Torsten %A Li, Man %A Lieverse, Aloysius %A Lindgren, Cecilia M %A Lyssenko, Valeriya %A Marre, Michel %A Meitinger, Thomas %A Midthjell, Kristian %A Morken, Mario A %A Narisu, Narisu %A Nilsson, Peter %A Owen, Katharine R %A Payne, Felicity %A Petersen, Ann-Kristin %A Platou, Carl %A Proença, Christine %A Prokopenko, Inga %A Rathmann, Wolfgang %A Rayner, N William %A Robertson, Neil R %A Rocheleau, Ghislain %A Roden, Michael %A Sampson, Michael J %A Saxena, Richa %A Shields, Beverley M %A Shrader, Peter %A Sigurdsson, Gunnar %A Sparsø, Thomas %A Strassburger, Klaus %A Stringham, Heather M %A Sun, Qi %A Swift, Amy J %A Thorand, Barbara %A Tichet, Jean %A Tuomi, Tiinamaija %A van Dam, Rob M %A van Haeften, Timon W %A van Herpt, Thijs %A van Vliet-Ostaptchouk, Jana V %A Walters, G Bragi %A Weedon, Michael N %A Wijmenga, Cisca %A Witteman, Jacqueline %A Bergman, Richard N %A Cauchi, Stephane %A Collins, Francis S %A Gloyn, Anna L %A Gyllensten, Ulf %A Hansen, Torben %A Hide, Winston A %A Hitman, Graham A %A Hofman, Albert %A Hunter, David J %A Hveem, Kristian %A Laakso, Markku %A Morris, Andrew D %A Palmer, Colin N A %A Rudan, Igor %A Sijbrands, Eric %A Stein, Lincoln D %A Tuomilehto, Jaakko %A Uitterlinden, Andre %A Walker, Mark %A Watanabe, Richard M %A Abecasis, Goncalo R %A Boehm, Bernhard O %A Campbell, Harry %A Daly, Mark J %A Hattersley, Andrew T %A Pedersen, Oluf %A Barroso, Inês %A Groop, Leif %A Sladek, Rob %A Thorsteinsdottir, Unnur %A Wilson, James F %A Illig, Thomas %A Froguel, Philippe %A van Duijn, Cornelia M %A Stefansson, Kari %A Altshuler, David %A Boehnke, Michael %A McCarthy, Mark I %A Soranzo, Nicole %A Wheeler, Eleanor %A Glazer, Nicole L %A Bouatia-Naji, Nabila %A Mägi, Reedik %A Randall, Joshua %A Elliott, Paul %A Rybin, Denis %A Dehghan, Abbas %A Hottenga, Jouke Jan %A Song, Kijoung %A Goel, Anuj %A Lajunen, Taina %A Doney, Alex %A Cavalcanti-Proença, Christine %A Kumari, Meena %A Timpson, Nicholas J %A Zabena, Carina %A Ingelsson, Erik %A An, Ping %A O'Connell, Jeffrey %A Luan, Jian'an %A Elliott, Amanda %A McCarroll, Steven A %A Roccasecca, Rosa Maria %A Pattou, François %A Sethupathy, Praveen %A Ariyurek, Yavuz %A Barter, Philip %A Beilby, John P %A Ben-Shlomo, Yoav %A Bergmann, Sven %A Bochud, Murielle %A Bonnefond, Amélie %A Borch-Johnsen, Knut %A Böttcher, Yvonne %A Brunner, Eric %A Bumpstead, Suzannah J %A Chen, Yii-Der Ida %A Chines, Peter %A Clarke, Robert %A Coin, Lachlan J M %A Cooper, Matthew N %A Crisponi, Laura %A Day, Ian N M %A de Geus, Eco J C %A Delplanque, Jerome %A Fedson, Annette C %A Fischer-Rosinsky, Antje %A Forouhi, Nita G %A Franzosi, Maria Grazia %A Galan, Pilar %A Goodarzi, Mark O %A Graessler, Jürgen %A Grundy, Scott %A Gwilliam, Rhian %A Hallmans, Göran %A Hammond, Naomi %A Han, Xijing %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heath, Simon C %A Hercberg, Serge %A Hillman, David R %A Hingorani, Aroon D %A Hui, Jennie %A Hung, Joe %A Kaakinen, Marika %A Kaprio, Jaakko %A Kesaniemi, Y Antero %A Kivimaki, Mika %A Knight, Beatrice %A Koskinen, Seppo %A Kovacs, Peter %A Kyvik, Kirsten Ohm %A Lathrop, G Mark %A Lawlor, Debbie A %A Le Bacquer, Olivier %A Lecoeur, Cécile %A Li, Yun %A Mahley, Robert %A Mangino, Massimo %A Martínez-Larrad, María Teresa %A McAteer, Jarred B %A McPherson, Ruth %A Meisinger, Christa %A Melzer, David %A Meyre, David %A Mitchell, Braxton D %A Mukherjee, Sutapa %A Naitza, Silvia %A Neville, Matthew J %A Orrù, Marco %A Pakyz, Ruth %A Paolisso, Giuseppe %A Pattaro, Cristian %A Pearson, Daniel %A Peden, John F %A Pedersen, Nancy L %A Pfeiffer, Andreas F H %A Pichler, Irene %A Polasek, Ozren %A Posthuma, Danielle %A Potter, Simon C %A Pouta, Anneli %A Province, Michael A %A Rayner, Nigel W %A Rice, Kenneth %A Ripatti, Samuli %A Rivadeneira, Fernando %A Rolandsson, Olov %A Sandbaek, Annelli %A Sandhu, Manjinder %A Sanna, Serena %A Sayer, Avan Aihie %A Scheet, Paul %A Seedorf, Udo %A Sharp, Stephen J %A Shields, Beverley %A Sigurðsson, Gunnar %A Sijbrands, Eric J G %A Silveira, Angela %A Simpson, Laila %A Singleton, Andrew %A Smith, Nicholas L %A Sovio, Ulla %A Swift, Amy %A Syddall, Holly %A Syvänen, Ann-Christine %A Tönjes, Anke %A Uitterlinden, André G %A van Dijk, Ko Willems %A Varma, Dhiraj %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogelzangs, Nicole %A Waeber, Gérard %A Wagner, Peter J %A Walley, Andrew %A Ward, Kim L %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Witteman, Jaqueline C M %A Yarnell, John W G %A Zelenika, Diana %A Zethelius, Björn %A Zhai, Guangju %A Zhao, Jing Hua %A Zillikens, M Carola %A Borecki, Ingrid B %A Meneton, Pierre %A Magnusson, Patrik K E %A Nathan, David M %A Williams, Gordon H %A Silander, Kaisa %A Bornstein, Stefan R %A Schwarz, Peter %A Spranger, Joachim %A Karpe, Fredrik %A Shuldiner, Alan R %A Cooper, Cyrus %A Serrano-Ríos, Manuel %A Lind, Lars %A Palmer, Lyle J %A Hu, Frank B %A Franks, Paul W %A Ebrahim, Shah %A Marmot, Michael %A Kao, W H Linda %A Pramstaller, Peter Paul %A Wright, Alan F %A Stumvoll, Michael %A Hamsten, Anders %A Buchanan, Thomas A %A Valle, Timo T %A Rotter, Jerome I %A Penninx, Brenda W J H %A Boomsma, Dorret I %A Cao, Antonio %A Scuteri, Angelo %A Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Peltonen, Leena %A Mooser, Vincent %A Sladek, Robert %A Musunuru, Kiran %A Smith, Albert V %A Edmondson, Andrew C %A Stylianou, Ioannis M %A Koseki, Masahiro %A Pirruccello, James P %A Chasman, Daniel I %A Johansen, Christopher T %A Fouchier, Sigrid W %A Peloso, Gina M %A Barbalic, Maja %A Ricketts, Sally L %A Bis, Joshua C %A Feitosa, Mary F %A Orho-Melander, Marju %A Melander, Olle %A Li, Xiaohui %A Li, Mingyao %A Cho, Yoon Shin %A Go, Min Jin %A Kim, Young Jin %A Lee, Jong-Young %A Park, Taesung %A Kim, Kyunga %A Sim, Xueling %A Ong, Rick Twee-Hee %A Croteau-Chonka, Damien C %A Lange, Leslie A %A Smith, Joshua D %A Ziegler, Andreas %A Zhang, Weihua %A Zee, Robert Y L %A Whitfield, John B %A Thompson, John R %A Surakka, Ida %A Spector, Tim D %A Smit, Johannes H %A Sinisalo, Juha %A Scott, James %A Saharinen, Juha %A Sabatti, Chiara %A Rose, Lynda M %A Roberts, Robert %A Rieder, Mark %A Parker, Alex N %A Paré, Guillaume %A O'Donnell, Christopher J %A Nieminen, Markku S %A Nickerson, Deborah A %A Montgomery, Grant W %A McArdle, Wendy %A Masson, David %A Martin, Nicholas G %A Marroni, Fabio %A Lucas, Gavin %A Luben, Robert %A Lokki, Marja-Liisa %A Lettre, Guillaume %A Launer, Lenore J %A Lakatta, Edward G %A Laaksonen, Reijo %A Kyvik, Kirsten O %A König, Inke R %A Khaw, Kay-Tee %A Kaplan, Lee M %A Johansson, Asa %A Janssens, A Cecile J W %A Igl, Wilmar %A Hovingh, G Kees %A Hengstenberg, Christian %A Havulinna, Aki S %A Hastie, Nicholas D %A Harris, Tamara B %A Haritunians, Talin %A Hall, Alistair S %A Groop, Leif C %A Gonzalez, Elena %A Freimer, Nelson B %A Erdmann, Jeanette %A Ejebe, Kenechi G %A Döring, Angela %A Dominiczak, Anna F %A Demissie, Serkalem %A Deloukas, Panagiotis %A de Faire, Ulf %A Crawford, Gabriel %A Chen, Yii-der I %A Caulfield, Mark J %A Boekholdt, S Matthijs %A Assimes, Themistocles L %A Quertermous, Thomas %A Seielstad, Mark %A Wong, Tien Y %A Tai, E-Shyong %A Feranil, Alan B %A Kuzawa, Christopher W %A Taylor, Herman A %A Gabriel, Stacey B %A Holm, Hilma %A Gudnason, Vilmundur %A Krauss, Ronald M %A Ordovas, Jose M %A Munroe, Patricia B %A Kooner, Jaspal S %A Tall, Alan R %A Hegele, Robert A %A Kastelein, John J P %A Schadt, Eric E %A Strachan, David P %A Reilly, Muredach P %A Samani, Nilesh J %A Schunkert, Heribert %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Ridker, Paul M %A Rader, Daniel J %A Kathiresan, Sekar %K Adiponectin %K African Americans %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Tolerance Test %K Humans %K Insulin Resistance %K Male %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Waist-Hip Ratio %X

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.

%B PLoS Genet %V 8 %P e1002607 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract %R 10.1371/journal.pgen.1002607 %0 Journal Article %J J Am Coll Cardiol %D 2012 %T Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults. %A deFilippi, Christopher R %A de Lemos, James A %A Tkaczuk, Andrew T %A Christenson, Robert H %A Carnethon, Mercedes R %A Siscovick, David S %A Gottdiener, John S %A Seliger, Stephen L %K Aged %K Biomarkers %K Female %K Heart Failure %K Humans %K Male %K Motor Activity %K Natriuretic Peptide, Brain %K Peptide Fragments %K Risk Assessment %K Troponin %X

OBJECTIVES: The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults.

BACKGROUND: Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified.

METHODS: NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25% increment from baseline to ≥190 pg/ml and for cTnT as a >50% increment from baseline in participants with detectable levels (≥3 pg/ml).

RESULTS: A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk.

CONCLUSIONS: These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.

%B J Am Coll Cardiol %V 60 %P 2539-47 %8 2012 Dec 18 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/23158528?dopt=Abstract %R 10.1016/j.jacc.2012.08.1006 %0 Journal Article %J Diabetes Care %D 2012 %T Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults. %A Djoussé, Luc %A Khawaja, Owais %A Bartz, Traci M %A Biggs, Mary L %A Ix, Joachim H %A Zieman, Susan J %A Kizer, Jorge R %A Tracy, Russell P %A Siscovick, David S %A Mukamal, Kenneth J %K Aged %K Aged, 80 and over %K Blood Glucose %K Body Mass Index %K Diabetes Mellitus %K Fatty Acid-Binding Proteins %K Fatty Acids, Nonesterified %K Female %K Humans %K Male %K Prospective Studies %X

OBJECTIVE: To examine the relation of fatty acid-binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.

RESEARCH DESIGN AND METHODS: We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992-2007) based on the use of hypoglycemic medications, fasting glucose ≥ 126 mg/dL, or nonfasting glucose ≥ 200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.

RESULTS: Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10-1.65) for women and 1.45 (1.13-1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m(2) (HR per SD: 1.78 [95% CI 1.13-2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P(trend) = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12-2.53), and 1.63 (1.07-2.50) across consecutive tertiles of NEFA (P(trend) = 0.03).

CONCLUSIONS: Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.

%B Diabetes Care %V 35 %P 1701-7 %8 2012 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22584136?dopt=Abstract %R 10.2337/dc11-1690 %0 Journal Article %J Am J Cardiol %D 2012 %T Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study). %A Khawaja, Owais %A Bartz, Traci M %A Ix, Joachim H %A Heckbert, Susan R %A Kizer, Jorge R %A Zieman, Susan J %A Mukamal, Kenneth J %A Tracy, Russell P %A Siscovick, David S %A Djoussé, Luc %K Aged %K Atrial Fibrillation %K C-Reactive Protein %K Diabetes Mellitus, Type 2 %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Lipoproteins, HDL %K Lipoproteins, LDL %K Male %K Natriuretic Peptide, Brain %K Obesity %K Peptide Fragments %K Prospective Studies %K Sex Factors %K Triglycerides %K United States %X

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women ≥65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 ± 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.

%B Am J Cardiol %V 110 %P 212-6 %8 2012 Jul 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22503582?dopt=Abstract %R 10.1016/j.amjcard.2012.03.010 %0 Journal Article %J Ann Intern Med %D 2012 %T Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. %A de Boer, Ian H %A Levin, Gregory %A Robinson-Cohen, Cassianne %A Biggs, Mary L %A Hoofnagle, Andy N %A Siscovick, David S %A Kestenbaum, Bryan %K Aged %K Cause of Death %K Female %K Follow-Up Studies %K Hip Fractures %K Humans %K Male %K Myocardial Infarction %K Neoplasms %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Seasons %K United States %K Vitamin D %K Vitamin D Deficiency %X

BACKGROUND: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration.

OBJECTIVE: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.

DESIGN: Cohort study.

SETTING: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.

PARTICIPANTS: 1621 white older adults.

MEASUREMENTS: Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death.

RESULTS: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.

LIMITATION: The observational study was restricted to white participants.

CONCLUSION: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk.

PRIMARY FUNDING SOURCE: National Institutes of Health.

%B Ann Intern Med %V 156 %P 627-34 %8 2012 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22547472?dopt=Abstract %R 10.7326/0003-4819-156-9-201205010-00004 %0 Journal Article %J Diabetes Care %D 2012 %T Total and high-molecular-weight adiponectin and risk of incident diabetes in older people. %A Kizer, Jorge R %A Arnold, Alice M %A Benkeser, David %A Ix, Joachim H %A Djoussé, Luc %A Zieman, Susan J %A Barzilay, Joshua I %A Tracy, Russell P %A Mantzoros, Christos S %A Siscovick, David S %A Mukamal, Kenneth J %K Adiponectin %K Aged %K Diabetes Mellitus %K Female %K Humans %K Male %K Risk Factors %X

OBJECTIVE: To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.

RESEARCH DESIGN AND METHODS: Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.

RESULTS: Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39-0.63]) and HMW adiponectin (0.42 [0.32-0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.

CONCLUSIONS: In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.

%B Diabetes Care %V 35 %P 415-23 %8 2012 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22148099?dopt=Abstract %R 10.2337/dc11-1519 %0 Journal Article %J Circ Arrhythm Electrophysiol %D 2012 %T Trans-fatty acid consumption and heart rate variability in 2 separate cohorts of older and younger adults. %A Soares-Miranda, Luisa %A Stein, Phyllis K %A Imamura, Fumiaki %A Sattelmair, Jacob %A Lemaitre, Rozenn N %A Siscovick, David S %A Mota, Jorge %A Mozaffarian, Dariush %K Adolescent %K Age Factors %K Aged %K Aging %K Arrhythmias, Cardiac %K Cohort Studies %K Cross-Sectional Studies %K Dietary Fats %K Electrocardiography, Ambulatory %K Feeding Behavior %K Female %K Heart Rate %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Multivariate Analysis %K Portugal %K Predictive Value of Tests %K Prospective Studies %K Risk Assessment %K Risk Factors %K Surveys and Questionnaires %K Trans Fatty Acids %K United States %K Young Adult %X

BACKGROUND: Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cell membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain understudied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, was independently associated with HRV in 2 independent cohorts in the United States and Portugal.

METHODS AND RESULTS: In 2 independent cohorts of older US adults (Cardiovascular Health Study [CHS], age 72±5 years, 1989/1995) and young Portuguese adults (Porto, age 19±2 years, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2 but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (n=1076) and repeated short-term (5-minute) ECGs in Porto (n=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour SD of all normal-to-normal intervals both cross-sectionally (-12%; 95% CI, -19% to -6%; P=0.001) and longitudinally (-15%; 95% CI, -25% to -4%; P= 0.009) and lower 24-hour SD of 5-minute average N-N intervals and mean of the 5-minute SD of N-N intervals calculated over 24 hours (P<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV in particular time-domain indices (24-hour SD of all normal-to-normal intervals, SD of 5-minute average N-N intervals, mean of the 5-minute SD of N-N intervals calculated over 24 hours; P<0.05 each). In Porto, each higher SD TFA consumption was associated with 4% lower 5-minute 24-hour SD of all normal-to-normal intervals (95% CI, -8% to -1%; P=0.04) and 7% lower 5-minute square root of the mean of the squares of successive N-N differences (95% CI, -13% to -1%; P=0.04).

CONCLUSIONS: Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV-related mechanisms, whereby trans-18:2 may increase arrhythmic risk.

%B Circ Arrhythm Electrophysiol %V 5 %P 728-38 %8 2012 Aug 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22772898?dopt=Abstract %R 10.1161/CIRCEP.111.966259 %0 Journal Article %J Cytokine %D 2012 %T Transforming growth factor beta-1 and incidence of heart failure in older adults: the Cardiovascular Health Study. %A Glazer, Nicole L %A Macy, Elizabeth M %A Lumley, Thomas %A Smith, Nicholas L %A Reiner, Alex P %A Psaty, Bruce M %A King, George L %A Tracy, Russell P %A Siscovick, David S %K Aged %K Case-Control Studies %K Health %K Heart Failure %K Humans %K Incidence %K Transforming Growth Factor beta1 %K United States %X

CONTEXT: Transforming growth factor-beta1 (TGF-B1) is a highly pleiotropic cytokine whose functions include a central role in the induction of fibrosis.

OBJECTIVE: To investigate the hypothesis that elevated plasma levels of TGF-B1 are positively associated with incident heart failure (HF).

PARTICIPANTS AND METHODS: The hypotheses were tested using a two-phase case-control study design, ancillary to the Cardiovascular Health Study - a longitudinal, population-based cohort study. Cases were defined as having an incident HF event after their 1992-1993 exam and controls were free of HF at follow-up. TGF-B1 was measured using plasma collected in 1992-1993 and data from 89 cases and 128 controls were used for analysis. The association between TGF-B1 and risk of HF was evaluated using the weighted likelihood method, and odds ratios (OR) for risk of HF were calculated for TGF-B1 as a continuous linear variable and across quartiles of TGF-B1.

RESULTS: The OR for HF was 1.88 (95% confidence intervals [CI] 1.26-2.81) for each nanogram increase in TGF-B1, and the OR for the highest quartile (compared to the lowest) of TGF-B1 was 5.79 (95% CI 1.65-20.34), after adjustment for age, sex, C-reactive protein, platelet count and digoxin use. Further adjustment with other covariates did not change the results.

CONCLUSIONS: Higher levels of plasma TGF-B1 were associated with an increased risk of incident heart failure among older adults. However, further study is needed in larger samples to confirm these findings.

%B Cytokine %V 60 %P 341-5 %8 2012 Nov %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22878343?dopt=Abstract %R 10.1016/j.cyto.2012.07.013 %0 Journal Article %J J Am Heart Assoc %D 2013 %T Associations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study. %A Fretts, Amanda M %A Mozaffarian, Dariush %A Siscovick, David S %A Heckbert, Susan R %A McKnight, Barbara %A King, Irena B %A Rimm, Eric B %A Psaty, Bruce M %A Sacks, Frank M %A Song, Xiaoling %A Spiegelman, Donna %A Lemaitre, Rozenn N %K Age Factors %K Aged %K Aged, 80 and over %K alpha-Linolenic Acid %K Atrial Fibrillation %K Biomarkers %K Diet %K Female %K Humans %K Incidence %K Linear Models %K Longitudinal Studies %K Male %K Nutritional Status %K Phospholipids %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

BACKGROUND: Few studies have examined the relationship of α-linolenic acid (ALA 18:3n-3), an intermediate-chain essential n-3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).

METHODS AND RESULTS: The study population included participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95% CI, 0.90 to 1.37), 1.09 (95% CI, 0.88 to 1.35), and 0.92 (95% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.

CONCLUSIONS: Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.

%B J Am Heart Assoc %V 2 %P e003814 %8 2013 Jan 31 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23525429?dopt=Abstract %R 10.1161/JAHA.112.003814 %0 Journal Article %J Ann Intern Med %D 2013 %T Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. %A Dewland, Thomas A %A Vittinghoff, Eric %A Mandyam, Mala C %A Heckbert, Susan R %A Siscovick, David S %A Stein, Phyllis K %A Psaty, Bruce M %A Sotoodehnia, Nona %A Gottdiener, John S %A Marcus, Gregory M %K Aged %K Atrial Fibrillation %K Atrial Function %K Cause of Death %K Electrocardiography %K Female %K Humans %K Male %K Models, Statistical %K Myocardial Contraction %K Prospective Studies %K Risk Assessment %X

BACKGROUND: Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.

OBJECTIVE: To investigate whether PAC count improves model performance for AF risk.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PATIENTS: A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.

MEASUREMENTS: The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.

RESULTS: In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h.

LIMITATION: This study does not establish a causal link between PACs and AF.

CONCLUSION: The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.

PRIMARY FUNDING SOURCE: American Heart Association, Joseph Drown Foundation, and National Institutes of Health.

%B Ann Intern Med %V 159 %P 721-8 %8 2013 Dec 03 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24297188?dopt=Abstract %R 10.7326/0003-4819-159-11-201312030-00004 %0 Journal Article %J PLoS One %D 2013 %T Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. %A Grove, Megan L %A Yu, Bing %A Cochran, Barbara J %A Haritunians, Talin %A Bis, Joshua C %A Taylor, Kent D %A Hansen, Mark %A Borecki, Ingrid B %A Cupples, L Adrienne %A Fornage, Myriam %A Gudnason, Vilmundur %A Harris, Tamara B %A Kathiresan, Sekar %A Kraaij, Robert %A Launer, Lenore J %A Levy, Daniel %A Liu, Yongmei %A Mosley, Thomas %A Peloso, Gina M %A Psaty, Bruce M %A Rich, Stephen S %A Rivadeneira, Fernando %A Siscovick, David S %A Smith, Albert V %A Uitterlinden, Andre %A van Duijn, Cornelia M %A Wilson, James G %A O'Donnell, Christopher J %A Rotter, Jerome I %A Boerwinkle, Eric %K Aging %K Alleles %K Cluster Analysis %K Cohort Studies %K Continental Population Groups %K Exome %K Female %K Gene Frequency %K Genomics %K Genotype %K Heart %K Humans %K Male %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K Sample Size %K Self Report %K Sequence Analysis, DNA %X

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

%B PLoS One %V 8 %P e68095 %8 2013 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23874508?dopt=Abstract %R 10.1371/journal.pone.0068095 %0 Journal Article %J Am J Hypertens %D 2013 %T Blood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study. %A Rifkin, Dena E %A Katz, Ronit %A Chonchol, Michel %A Shlipak, Michael G %A Sarnak, Mark J %A Fried, Linda F %A Newman, Anne B %A Siscovick, David S %A Peralta, Carmen A %K Aged %K Blood Pressure %K Cohort Studies %K Cystatin C %K Diastole %K Disease Progression %K Female %K Glomerular Filtration Rate %K Humans %K Hypertension %K Logistic Models %K Longitudinal Studies %K Male %K Pulse %K Renal Insufficiency, Chronic %K Systole %X

BACKGROUND: Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.

METHODS: We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.

RESULTS: Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (-0.19, -0.08, P < 0.001) and 0.15-ml/min/year faster decline (-0.21, -0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, -0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.

CONCLUSIONS: Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.

%B Am J Hypertens %V 26 %P 1037-44 %8 2013 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23709568?dopt=Abstract %R 10.1093/ajh/hpt067 %0 Journal Article %J Metabolism %D 2013 %T Circulating 25-hydroxyvitamin D is associated with insulin resistance cross-sectionally but not longitudinally in older adults: The Cardiovascular Health Study. %A Danziger, John %A Biggs, Mary L %A Niemi, Matt %A Ix, Joachim H %A Kizer, Jorge R %A Djoussé, Luc %A de Boer, Ian H %A Siscovick, David S %A Kestenbaum, Bryan %A Mukamal, Kenneth J %K Adiposity %K Aged %K Anthropometry %K Cardiovascular Diseases %K Cross-Sectional Studies %K Exercise %K Female %K Humans %K Hydroxycholecalciferols %K Inflammation %K Insulin %K Insulin Resistance %K Longitudinal Studies %K Male %K Middle Aged %K Obesity %K Risk Factors %K Surveys and Questionnaires %X

BACKGROUND: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear.

OBJECTIVE: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults.

METHODS AND RESULTS: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis.

CONCLUSIONS: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.

%B Metabolism %V 62 %P 1788-94 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23987236?dopt=Abstract %R 10.1016/j.metabol.2013.07.008 %0 Journal Article %J J Am Heart Assoc %D 2013 %T Circulating omega-3 polyunsaturated fatty acids and subclinical brain abnormalities on MRI in older adults: the Cardiovascular Health Study. %A Virtanen, Jyrki K %A Siscovick, David S %A Lemaitre, Rozenn N %A Longstreth, William T %A Spiegelman, Donna %A Rimm, Eric B %A King, Irena B %A Mozaffarian, Dariush %K Aged %K Animals %K Biomarkers %K Brain %K Cross-Sectional Studies %K Fatty Acids, Omega-3 %K Female %K Fishes %K Humans %K Magnetic Resonance Imaging %K Male %K Prospective Studies %X

BACKGROUND: Consumption of tuna or other broiled or baked fish, but not fried fish, is associated with fewer subclinical brain abnormalities on magnetic resonance imaging (MRI). We investigated the association between plasma phospholipid omega-3 polyunsaturated fatty acids (PUFAs), objective biomarkers of exposure, and subclinical brain abnormalities on MRI.

METHODS AND RESULTS: In the community-based Cardiovascular Health Study, 3660 participants aged ≥ 65 underwent brain MRI in 1992-1994, and 2313 were rescanned 5 years later. MRIs were centrally read by neuroradiologists in a standardized, blinded manner. Participants with recognized transient ischemic attacks or stroke were excluded. Phospholipid PUFAs were measured in stored plasma collected in 1992-1993 and related to cross-sectional and longitudinal MRI findings. After multivariable adjustment, the odds ratio for having a prevalent subclinical infarct was 0.60 (95% CI, 0.44 to 0.82; P for trend = 0.001) in the highest versus lowest long-chain omega-3 PUFA quartile. Higher long-chain omega-3 PUFA content was also associated with better white matter grade, but not with sulcal or ventricular grades, markers of brain atrophy, or with incident subclinical infarcts. The phospholipid intermediate-chain omega-3 PUFA alpha-linolenic acid was associated only with modestly better sulcal and ventricular grades. However, this finding was not supported in the analyses with alpha-linolenic acid intake.

CONCLUSIONS: Among older adults, higher phospholipid long-chain omega-3 PUFA content was associated with lower prevalence of subclinical infarcts and better white matter grade on MRI. Our results support the beneficial effects of fish consumption, the major source of long-chain omega-3 PUFAs, on brain health in later life. The role of plant-derived alpha-linolenic acid in brain health requires further investigation.

%B J Am Heart Assoc %V 2 %P e000305 %8 2013 Oct 10 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24113325?dopt=Abstract %R 10.1161/JAHA.113.000305 %0 Journal Article %J Lipids %D 2013 %T Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults. %A Mukamal, Kenneth J %A Wilk, Jemma B %A Biggs, Mary L %A Jensen, Majken K %A Ix, Joachim H %A Kizer, Jorge R %A Tracy, Russell P %A Zieman, Susan J %A Mozaffarian, Dariush %A Psaty, Bruce M %A Siscovick, David S %A Djoussé, Luc %K African Americans %K Aged %K Aged, 80 and over %K Blood Glucose %K Body Mass Index %K Cohort Studies %K European Continental Ancestry Group %K Fatty Acid-Binding Proteins %K Female %K Gene Frequency %K Genetic Association Studies %K Haplotypes %K Humans %K Insulin %K Linkage Disequilibrium %K Male %K Polymorphism, Single Nucleotide %X

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.

%B Lipids %V 48 %P 1169-75 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24043587?dopt=Abstract %R 10.1007/s11745-013-3838-7 %0 Journal Article %J Am J Clin Nutr %D 2013 %T Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. %A van Meurs, Joyce B J %A Paré, Guillaume %A Schwartz, Stephen M %A Hazra, Aditi %A Tanaka, Toshiko %A Vermeulen, Sita H %A Cotlarciuc, Ioana %A Yuan, Xin %A Mälarstig, Anders %A Bandinelli, Stefania %A Bis, Joshua C %A Blom, Henk %A Brown, Morris J %A Chen, Constance %A Chen, Yii-Der %A Clarke, Robert J %A Dehghan, Abbas %A Erdmann, Jeanette %A Ferrucci, Luigi %A Hamsten, Anders %A Hofman, Albert %A Hunter, David J %A Goel, Anuj %A Johnson, Andrew D %A Kathiresan, Sekar %A Kampman, Ellen %A Kiel, Douglas P %A Kiemeney, Lambertus A L M %A Chambers, John C %A Kraft, Peter %A Lindemans, Jan %A McKnight, Barbara %A Nelson, Christopher P %A O'Donnell, Christopher J %A Psaty, Bruce M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rose, Lynda M %A Seedorf, Udo %A Siscovick, David S %A Schunkert, Heribert %A Selhub, Jacob %A Ueland, Per M %A Vollenweider, Peter %A Waeber, Gérard %A Waterworth, Dawn M %A Watkins, Hugh %A Witteman, Jacqueline C M %A den Heijer, Martin %A Jacques, Paul %A Uitterlinden, André G %A Kooner, Jaspal S %A Rader, Dan J %A Reilly, Muredach P %A Mooser, Vincent %A Chasman, Daniel I %A Samani, Nilesh J %A Ahmadi, Kourosh R %K Coronary Artery Disease %K Genes %K Genetic Loci %K Genetic Predisposition to Disease %K Genotype %K Homocysteine %K Humans %K Polymorphism, Genetic %K Risk Factors %X

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.

OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.

DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.

RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).

CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

%B Am J Clin Nutr %V 98 %P 668-76 %8 2013 Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23824729?dopt=Abstract %R 10.3945/ajcn.112.044545 %0 Journal Article %J J Am Soc Nephrol %D 2013 %T Common variants in Mendelian kidney disease genes and their association with renal function. %A Parsa, Afshin %A Fuchsberger, Christian %A Köttgen, Anna %A O'Seaghdha, Conall M %A Pattaro, Cristian %A de Andrade, Mariza %A Chasman, Daniel I %A Teumer, Alexander %A Endlich, Karlhans %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Kim, Young J %A Taliun, Daniel %A Li, Man %A Feitosa, Mary %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A Glazer, Nicole %A Isaacs, Aaron %A Rao, Madhumathi %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Couraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Hofer, Edith %A Hu, Frank %A Demirkan, Ayse %A Oostra, Ben A %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Giulianini, Franco %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Zgaga, Lina %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Stengel, Bénédicte %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Mitchell, Paul %A Ciullo, Marina %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline %A Hayward, Caroline %A Ridker, Paul M %A Bochud, Murielle %A Heid, Iris M %A Siscovick, David S %A Fox, Caroline S %A Kao, W Linda %A Böger, Carsten A %K Databases, Genetic %K European Continental Ancestry Group %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Mendelian Randomization Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %X

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.

%B J Am Soc Nephrol %V 24 %P 2105-17 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract %R 10.1681/ASN.2012100983 %0 Journal Article %J Eur J Heart Fail %D 2013 %T Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study. %A Djoussé, Luc %A Bartz, Traci M %A Ix, Joachim H %A Kochar, Jinesh %A Kizer, Jorge R %A Gottdiener, John S %A Tracy, Russell P %A Mozaffarian, Dariush %A Siscovick, David S %A Mukamal, Kenneth J %A Zieman, Susan J %K Aged %K Aged, 80 and over %K Body Mass Index %K Cohort Studies %K Fatty Acid-Binding Proteins %K Female %K Follow-Up Studies %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Male %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K United States %K Ventricular Function, Left %X

AIM: To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.

METHODS AND RESULTS: In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.

CONCLUSION: An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.

%B Eur J Heart Fail %V 15 %P 394-9 %8 2013 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23223158?dopt=Abstract %& 394 %R 10.1093/eurjhf/hfs196 %0 Journal Article %J Diabetes Care %D 2013 %T Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study. %A Jensen, Majken K %A Bartz, Traci M %A Mukamal, Kenneth J %A Djoussé, Luc %A Kizer, Jorge R %A Tracy, Russell P %A Zieman, Susan J %A Rimm, Eric B %A Siscovick, David S %A Shlipak, Michael %A Ix, Joachim H %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K Female %K Fetuins %K Humans %K Incidence %K Longitudinal Studies %K Male %K Risk Factors %X

OBJECTIVE: Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.

RESEARCH DESIGN AND METHODS: This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.

RESULTS: Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88-0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93-1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85-0.97) and 0.87 (0.79-0.95), respectively].

CONCLUSIONS: The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.

%B Diabetes Care %V 36 %P 1222-8 %8 2013 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23250801?dopt=Abstract %R 10.2337/dc12-1591 %0 Journal Article %J PLoS One %D 2013 %T Genetic loci for retinal arteriolar microcirculation. %A Sim, Xueling %A Jensen, Richard A %A Ikram, M Kamran %A Cotch, Mary Frances %A Li, Xiaohui %A Macgregor, Stuart %A Xie, Jing %A Smith, Albert Vernon %A Boerwinkle, Eric %A Mitchell, Paul %A Klein, Ronald %A Klein, Barbara E K %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A de Jong, Paulus T V M %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Launer, Lenore J %A Attia, John %A Baird, Paul N %A Harrap, Stephen %A Holliday, Elizabeth G %A Inouye, Michael %A Rochtchina, Elena %A Scott, Rodney J %A Viswanathan, Ananth %A Li, Guo %A Smith, Nicholas L %A Wiggins, Kerri L %A Kuo, Jane Z %A Taylor, Kent D %A Hewitt, Alex W %A Martin, Nicholas G %A Montgomery, Grant W %A Sun, Cong %A Young, Terri L %A Mackey, David A %A van Zuydam, Natalie R %A Doney, Alex S F %A Palmer, Colin N A %A Morris, Andrew D %A Rotter, Jerome I %A Tai, E Shyong %A Gudnason, Vilmundur %A Vingerling, Johannes R %A Siscovick, David S %A Wang, Jie Jin %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Arterioles %K Chromosomes, Human, Pair 5 %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K MEF2 Transcription Factors %K Microcirculation %K Middle Aged %K Models, Genetic %K Retinal Vessels %X

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.

%B PLoS One %V 8 %P e65804 %8 2013 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract %R 10.1371/journal.pone.0065804 %0 Journal Article %J Diabetes Care %D 2013 %T Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study. %A Jensen, Majken K %A Bartz, Traci M %A Djoussé, Luc %A Kizer, Jorge R %A Zieman, Susan J %A Rimm, Eric B %A Siscovick, David S %A Psaty, Bruce M %A Ix, Joachim H %A Mukamal, Kenneth J %K alpha-2-HS-Glycoprotein %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Genotype %K Humans %K Male %K Polymorphism, Single Nucleotide %X

OBJECTIVE: Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS: Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993.

RESULTS: Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant.

CONCLUSIONS: Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

%B Diabetes Care %V 36 %P 3121-7 %8 2013 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/23801724?dopt=Abstract %R 10.2337/dc12-2323 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. %A Köttgen, Anna %A Albrecht, Eva %A Teumer, Alexander %A Vitart, Veronique %A Krumsiek, Jan %A Hundertmark, Claudia %A Pistis, Giorgio %A Ruggiero, Daniela %A O'Seaghdha, Conall M %A Haller, Toomas %A Yang, Qiong %A Tanaka, Toshiko %A Johnson, Andrew D %A Kutalik, Zoltán %A Smith, Albert V %A Shi, Julia %A Struchalin, Maksim %A Middelberg, Rita P S %A Brown, Morris J %A Gaffo, Angelo L %A Pirastu, Nicola %A Li, Guo %A Hayward, Caroline %A Zemunik, Tatijana %A Huffman, Jennifer %A Yengo, Loic %A Zhao, Jing Hua %A Demirkan, Ayse %A Feitosa, Mary F %A Liu, Xuan %A Malerba, Giovanni %A Lopez, Lorna M %A van der Harst, Pim %A Li, Xinzhong %A Kleber, Marcus E %A Hicks, Andrew A %A Nolte, Ilja M %A Johansson, Asa %A Murgia, Federico %A Wild, Sarah H %A Bakker, Stephan J L %A Peden, John F %A Dehghan, Abbas %A Steri, Maristella %A Tenesa, Albert %A Lagou, Vasiliki %A Salo, Perttu %A Mangino, Massimo %A Rose, Lynda M %A Lehtimäki, Terho %A Woodward, Owen M %A Okada, Yukinori %A Tin, Adrienne %A Müller, Christian %A Oldmeadow, Christopher %A Putku, Margus %A Czamara, Darina %A Kraft, Peter %A Frogheri, Laura %A Thun, Gian Andri %A Grotevendt, Anne %A Gislason, Gauti Kjartan %A Harris, Tamara B %A Launer, Lenore J %A McArdle, Patrick %A Shuldiner, Alan R %A Boerwinkle, Eric %A Coresh, Josef %A Schmidt, Helena %A Schallert, Michael %A Martin, Nicholas G %A Montgomery, Grant W %A Kubo, Michiaki %A Nakamura, Yusuke %A Tanaka, Toshihiro %A Munroe, Patricia B %A Samani, Nilesh J %A Jacobs, David R %A Liu, Kiang %A D'Adamo, Pio %A Ulivi, Sheila %A Rotter, Jerome I %A Psaty, Bruce M %A Vollenweider, Peter %A Waeber, Gérard %A Campbell, Susan %A Devuyst, Olivier %A Navarro, Pau %A Kolcic, Ivana %A Hastie, Nicholas %A Balkau, Beverley %A Froguel, Philippe %A Esko, Tõnu %A Salumets, Andres %A Khaw, Kay Tee %A Langenberg, Claudia %A Wareham, Nicholas J %A Isaacs, Aaron %A Kraja, Aldi %A Zhang, Qunyuan %A Wild, Philipp S %A Scott, Rodney J %A Holliday, Elizabeth G %A Org, Elin %A Viigimaa, Margus %A Bandinelli, Stefania %A Metter, Jeffrey E %A Lupo, Antonio %A Trabetti, Elisabetta %A Sorice, Rossella %A Döring, Angela %A Lattka, Eva %A Strauch, Konstantin %A Theis, Fabian %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Bruinenberg, Marcel %A Stolk, Ronald P %A Kooner, Jaspal S %A Zhang, Weihua %A Winkelmann, Bernhard R %A Boehm, Bernhard O %A Lucae, Susanne %A Penninx, Brenda W %A Smit, Johannes H %A Curhan, Gary %A Mudgal, Poorva %A Plenge, Robert M %A Portas, Laura %A Persico, Ivana %A Kirin, Mirna %A Wilson, James F %A Mateo Leach, Irene %A van Gilst, Wiek H %A Goel, Anuj %A Ongen, Halit %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Imboden, Medea %A von Eckardstein, Arnold %A Cucca, Francesco %A Nagaraja, Ramaiah %A Piras, Maria Grazia %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Ernst, Florian %A Farrington, Susan M %A Theodoratou, Evropi %A Prokopenko, Inga %A Stumvoll, Michael %A Jula, Antti %A Perola, Markus %A Salomaa, Veikko %A Shin, So-Youn %A Spector, Tim D %A Sala, Cinzia %A Ridker, Paul M %A Kähönen, Mika %A Viikari, Jorma %A Hengstenberg, Christian %A Nelson, Christopher P %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Singleton, Andrew B %A Kamatani, Naoyuki %A Zeller, Tanja %A Burnier, Michel %A Attia, John %A Laan, Maris %A Klopp, Norman %A Hillege, Hans L %A Kloiber, Stefan %A Choi, Hyon %A Pirastu, Mario %A Tore, Silvia %A Probst-Hensch, Nicole M %A Völzke, Henry %A Gudnason, Vilmundur %A Parsa, Afshin %A Schmidt, Reinhold %A Whitfield, John B %A Fornage, Myriam %A Gasparini, Paolo %A Siscovick, David S %A Polasek, Ozren %A Campbell, Harry %A Rudan, Igor %A Bouatia-Naji, Nabila %A Metspalu, Andres %A Loos, Ruth J F %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Wolffenbuttel, Bruce H R %A Chambers, John C %A März, Winfried %A Pramstaller, Peter P %A Snieder, Harold %A Gyllensten, Ulf %A Wright, Alan F %A Navis, Gerjan %A Watkins, Hugh %A Witteman, Jacqueline C M %A Sanna, Serena %A Schipf, Sabine %A Dunlop, Malcolm G %A Tönjes, Anke %A Ripatti, Samuli %A Soranzo, Nicole %A Toniolo, Daniela %A Chasman, Daniel I %A Raitakari, Olli %A Kao, W H Linda %A Ciullo, Marina %A Fox, Caroline S %A Caulfield, Mark %A Bochud, Murielle %A Gieger, Christian %K Analysis of Variance %K European Continental Ancestry Group %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Glucose %K Gout %K Humans %K Inhibins %K Polymorphism, Single Nucleotide %K Signal Transduction %K Uric Acid %X

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.

%B Nat Genet %V 45 %P 145-54 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract %R 10.1038/ng.2500 %0 Journal Article %J PLoS One %D 2013 %T Genome-wide association study of retinopathy in individuals without diabetes. %A Jensen, Richard A %A Sim, Xueling %A Li, Xiaohui %A Cotch, Mary Frances %A Ikram, M Kamran %A Holliday, Elizabeth G %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore J %A Smith, Albert Vernon %A Boerwinkle, Eric %A Cheung, Ning %A Hewitt, Alex W %A Liew, Gerald %A Mitchell, Paul %A Wang, Jie Jin %A Attia, John %A Scott, Rodney %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Taylor, Kent %A Hofman, Albert %A de Jong, Paulus T V M %A Rivadeneira, Fernando %A Uitterlinden, André G %A Tay, Wan-Ting %A Teo, Yik Ying %A Seielstad, Mark %A Liu, Jianjun %A Cheng, Ching-Yu %A Saw, Seang-Mei %A Aung, Tin %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Nalls, Mike A %A Wiggins, Kerri L %A Kuo, Jane Z %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Klein, Ronald %A Siscovick, David S %A Rotter, Jerome I %A Tai, E Shong %A Vingerling, Johannes %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Female %K Genome-Wide Association Study %K Genotype %K Histone Deacetylases %K Humans %K Hypertension %K Male %K Polymorphism, Single Nucleotide %K Repressor Proteins %K Retinal Diseases %X

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

%B PLoS One %V 8 %P e54232 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23393555?dopt=Abstract %R 10.1371/journal.pone.0054232 %0 Journal Article %J Am J Clin Nutr %D 2013 %T Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. %A Tanaka, Toshiko %A Ngwa, Julius S %A van Rooij, Frank J A %A Zillikens, M Carola %A Wojczynski, Mary K %A Frazier-Wood, Alexis C %A Houston, Denise K %A Kanoni, Stavroula %A Lemaitre, Rozenn N %A Luan, Jian'an %A Mikkilä, Vera %A Renstrom, Frida %A Sonestedt, Emily %A Zhao, Jing Hua %A Chu, Audrey Y %A Qi, Lu %A Chasman, Daniel I %A de Oliveira Otto, Marcia C %A Dhurandhar, Emily J %A Feitosa, Mary F %A Johansson, Ingegerd %A Khaw, Kay-Tee %A Lohman, Kurt K %A Manichaikul, Ani %A McKeown, Nicola M %A Mozaffarian, Dariush %A Singleton, Andrew %A Stirrups, Kathleen %A Viikari, Jorma %A Ye, Zheng %A Bandinelli, Stefania %A Barroso, Inês %A Deloukas, Panos %A Forouhi, Nita G %A Hofman, Albert %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A North, Kari E %A Dimitriou, Maria %A Hallmans, Göran %A Kähönen, Mika %A Langenberg, Claudia %A Ordovas, Jose M %A Uitterlinden, André G %A Hu, Frank B %A Kalafati, Ioanna-Panagiota %A Raitakari, Olli %A Franco, Oscar H %A Johnson, Andrew %A Emilsson, Valur %A Schrack, Jennifer A %A Semba, Richard D %A Siscovick, David S %A Arnett, Donna K %A Borecki, Ingrid B %A Franks, Paul W %A Kritchevsky, Stephen B %A Lehtimäki, Terho %A Loos, Ruth J F %A Orho-Melander, Marju %A Rotter, Jerome I %A Wareham, Nicholas J %A Witteman, Jacqueline C M %A Ferrucci, Luigi %A Dedoussis, George %A Cupples, L Adrienne %A Nettleton, Jennifer A %K Alleles %K Atherosclerosis %K Body Mass Index %K Dietary Carbohydrates %K Dietary Fats %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Fibroblast Growth Factors %K Follow-Up Studies %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Life Style %K Obesity %K Polymorphism, Single Nucleotide %K Prospective Studies %K Quantitative Trait Loci %K Surveys and Questionnaires %X

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).

%B Am J Clin Nutr %V 97 %P 1395-402 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23636237?dopt=Abstract %R 10.3945/ajcn.112.052183 %0 Journal Article %J J Nutr %D 2013 %T Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies. %A Hruby, Adela %A Ngwa, Julius S %A Renstrom, Frida %A Wojczynski, Mary K %A Ganna, Andrea %A Hallmans, Göran %A Houston, Denise K %A Jacques, Paul F %A Kanoni, Stavroula %A Lehtimäki, Terho %A Lemaitre, Rozenn N %A Manichaikul, Ani %A North, Kari E %A Ntalla, Ioanna %A Sonestedt, Emily %A Tanaka, Toshiko %A van Rooij, Frank J A %A Bandinelli, Stefania %A Djoussé, Luc %A Grigoriou, Efi %A Johansson, Ingegerd %A Lohman, Kurt K %A Pankow, James S %A Raitakari, Olli T %A Riserus, Ulf %A Yannakoulia, Mary %A Zillikens, M Carola %A Hassanali, Neelam %A Liu, Yongmei %A Mozaffarian, Dariush %A Papoutsakis, Constantina %A Syvänen, Ann-Christine %A Uitterlinden, André G %A Viikari, Jorma %A Groves, Christopher J %A Hofman, Albert %A Lind, Lars %A McCarthy, Mark I %A Mikkilä, Vera %A Mukamal, Kenneth %A Franco, Oscar H %A Borecki, Ingrid B %A Cupples, L Adrienne %A Dedoussis, George V %A Ferrucci, Luigi %A Hu, Frank B %A Ingelsson, Erik %A Kähönen, Mika %A Kao, W H Linda %A Kritchevsky, Stephen B %A Orho-Melander, Marju %A Prokopenko, Inga %A Rotter, Jerome I %A Siscovick, David S %A Witteman, Jacqueline C M %A Franks, Paul W %A Meigs, James B %A McKeown, Nicola M %A Nettleton, Jennifer A %K Blood Glucose %K Female %K Genetic Loci %K Humans %K Insulin %K Magnesium %K Male %K Polymorphism, Single Nucleotide %K Trace Elements %K TRPM Cation Channels %X

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

%B J Nutr %V 143 %P 345-53 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23343670?dopt=Abstract %R 10.3945/jn.112.172049 %0 Journal Article %J Circulation %D 2013 %T Long-chain monounsaturated Fatty acids and incidence of congestive heart failure in 2 prospective cohorts. %A Imamura, Fumiaki %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Steffen, Lyn M %A Folsom, Aaron R %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Cross-Sectional Studies %K Dietary Fats %K Fatty Acids, Monounsaturated %K Feeding Behavior %K Female %K Heart Failure %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Nutrition Surveys %K Prospective Studies %K Risk Factors %K Stroke %X

BACKGROUND: Decades-old animal experiments suggested that dietary long-chain monounsaturated fatty acids (LCMUFAs) caused cardiotoxicity, leading, for example, development of Canola oil (Canadian oil low in erucic acid) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFAs are unknown.

METHODS AND RESULTS: We prospectively investigated the associations of plasma phospholipid LCMUFAs (20:1, 22:1, and 24:1), assessed as objective biomarkers of exposure, with incidence congestive heart failure in 2 independent cohorts: 3694 older adults (mean age, 75.2±5.2 years) in the Cardiovascular Health Study (CHS; 1992-2006) and 3577 middle-aged adults (mean age, 54.1±5.8 years) in the Atherosclerosis Risk in Communities Study, Minnesota subcohort (ARIC; 1987-2008). We further examined dietary correlates of circulating LCMUFAs in CHS and ARIC and US dietary sources of LCMUFAs in the 2003-2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 congestive heart failure events occurred during 39 238 person-years; in ARIC, 330 events congestive heart failure events occurred during 64 438 person-years. After multivariable adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident congestive heart failure in both CHS and ARIC; hazard ratios were 1.34 (95% confidence interval, 1.02-1.76) and 1.57 (95% confidence interval, 1.11-2.23) for highest versus lowest quintiles of 22:1, respectively, and 1.75 (95% confidence interval, 1.23-2.50) and 1.92 (95% confidence interval, 1.22-3.03) for 24:1, respectively (P for trend ≤0.03 each). A variety of foods were related to circulating LCMUFAs in CHS and ARIC, consistent with food sources of LCMUFAs in NHANES, including fish, poultry, meats, whole grains, and mustard.

CONCLUSIONS: Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident congestive heart failure in 2 independent cohorts, suggesting possible cardiotoxicity of LCMUFAs in humans.

%B Circulation %V 127 %P 1512-21, 1521e1-18 %8 2013 Apr 09 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/23487436?dopt=Abstract %& 1512 %R 10.1161/CIRCULATIONAHA.112.001197 %0 Journal Article %J PLoS Genet %D 2013 %T Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. %A O'Seaghdha, Conall M %A Wu, Hongsheng %A Yang, Qiong %A Kapur, Karen %A Guessous, Idris %A Zuber, Annie Mercier %A Köttgen, Anna %A Stoudmann, Candice %A Teumer, Alexander %A Kutalik, Zoltán %A Mangino, Massimo %A Dehghan, Abbas %A Zhang, Weihua %A Eiriksdottir, Gudny %A Li, Guo %A Tanaka, Toshiko %A Portas, Laura %A Lopez, Lorna M %A Hayward, Caroline %A Lohman, Kurt %A Matsuda, Koichi %A Padmanabhan, Sandosh %A Firsov, Dmitri %A Sorice, Rossella %A Ulivi, Sheila %A Brockhaus, A Catharina %A Kleber, Marcus E %A Mahajan, Anubha %A Ernst, Florian D %A Gudnason, Vilmundur %A Launer, Lenore J %A Mace, Aurelien %A Boerwinckle, Eric %A Arking, Dan E %A Tanikawa, Chizu %A Nakamura, Yusuke %A Brown, Morris J %A Gaspoz, Jean-Michel %A Theler, Jean-Marc %A Siscovick, David S %A Psaty, Bruce M %A Bergmann, Sven %A Vollenweider, Peter %A Vitart, Veronique %A Wright, Alan F %A Zemunik, Tatijana %A Boban, Mladen %A Kolcic, Ivana %A Navarro, Pau %A Brown, Edward M %A Estrada, Karol %A Ding, Jingzhong %A Harris, Tamara B %A Bandinelli, Stefania %A Hernandez, Dena %A Singleton, Andrew B %A Girotto, Giorgia %A Ruggiero, Daniela %A d'Adamo, Adamo Pio %A Robino, Antonietta %A Meitinger, Thomas %A Meisinger, Christa %A Davies, Gail %A Starr, John M %A Chambers, John C %A Boehm, Bernhard O %A Winkelmann, Bernhard R %A Huang, Jie %A Murgia, Federico %A Wild, Sarah H %A Campbell, Harry %A Morris, Andrew P %A Franco, Oscar H %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Völker, Uwe %A Hannemann, Anke %A Biffar, Reiner %A Hoffmann, Wolfgang %A Shin, So-Youn %A Lescuyer, Pierre %A Henry, Hughes %A Schurmann, Claudia %A Munroe, Patricia B %A Gasparini, Paolo %A Pirastu, Nicola %A Ciullo, Marina %A Gieger, Christian %A März, Winfried %A Lind, Lars %A Spector, Tim D %A Smith, Albert V %A Rudan, Igor %A Wilson, James F %A Polasek, Ozren %A Deary, Ian J %A Pirastu, Mario %A Ferrucci, Luigi %A Liu, Yongmei %A Kestenbaum, Bryan %A Kooner, Jaspal S %A Witteman, Jacqueline C M %A Nauck, Matthias %A Kao, W H Linda %A Wallaschofski, Henri %A Bonny, Olivier %A Fox, Caroline S %A Bochud, Murielle %K Animals %K Bone and Bones %K Bone Density %K Calcium %K European Continental Ancestry Group %K Gene Expression Regulation %K Genome-Wide Association Study %K Homeostasis %K Humans %K Kidney %K Mice %K Polymorphism, Single Nucleotide %X

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.

%B PLoS Genet %V 9 %P e1003796 %8 2013 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract %R 10.1371/journal.pgen.1003796 %0 Journal Article %J Cardiol Res Pract %D 2013 %T Plasma Fatty Acid binding protein 4 and risk of sudden cardiac death in older adults. %A Djoussé, Luc %A Maziarz, Marlena %A Biggs, Mary L %A Ix, Joachim H %A Zieman, Susan J %A Kizer, Jorge R %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %A Tracy, Russell P %A Mukamal, Kenneth J %A Siscovick, David S %A Sotoodehnia, Nona %X

Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95-1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07-1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62-1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.

%B Cardiol Res Pract %V 2013 %P 181054 %8 2013 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24455402?dopt=Abstract %R 10.1155/2013/181054 %0 Journal Article %J Circ Heart Fail %D 2013 %T Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study. %A Djoussé, Luc %A Benkeser, David %A Arnold, Alice %A Kizer, Jorge R %A Zieman, Susan J %A Lemaitre, Rozenn N %A Tracy, Russell P %A Gottdiener, John S %A Mozaffarian, Dariush %A Siscovick, David S %A Mukamal, Kenneth J %A Ix, Joachim H %K Aged %K Aged, 80 and over %K Biomarkers %K Comorbidity %K Fatty Acids, Nonesterified %K Female %K Heart Failure %K Humans %K Incidence %K Kaplan-Meier Estimate %K Linear Models %K Male %K Multivariate Analysis %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Time Factors %K United States %X

BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).

METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% confidence interval, 6%-19%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95% confidence interval, 1.09-1.23]).

CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.

%B Circ Heart Fail %V 6 %P 964-9 %8 2013 Sep 01 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23926204?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.113.000521 %0 Journal Article %J Ann Intern Med %D 2013 %T Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. %A Mozaffarian, Dariush %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Huang, Hongyan %A Sacks, Frank M %A Rimm, Eric B %A Wang, Molin %A Siscovick, David S %K Aged %K Biomarkers %K Cause of Death %K Coronary Disease %K Diet Records %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Fatty Acids, Omega-3 %K Fatty Acids, Unsaturated %K Feeding Behavior %K Female %K Humans %K Male %K Prospective Studies %K Risk Assessment %K Stroke %X

BACKGROUND: Long-chain ω-3 polyunsaturated fatty acids (ω3-PUFAs), including eicosapentaenoic acid (EPA) (20:5ω-3), docosapentaenoic acid (DPA) (22:5ω-3), and docosahexaenoic acid (DHA) (22:6ω-3), have been shown to reduce cardiovascular risk, but effects on cause-specific and total mortality and potential dose-responses remain controversial. Most observational studies have assessed self-reported dietary intake and most randomized trials have tested effects of adding supplements to dietary intake and evaluated secondary prevention, thus limiting inference for dietary ω3-PUFAs or primary prevention.

OBJECTIVE: To investigate associations of plasma phospholipid EPA, DPA, DHA, and total ω3-PUFA levels with total and cause-specific mortality among healthy older adults not receiving supplements.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PARTICIPANTS: 2692 U.S. adults aged 74 years (±5 years) without prevalent coronary heart disease (CHD), stroke, or heart failure at baseline.

MEASUREMENTS: Phospholipid fatty acid levels and cardiovascular risk factors were measured in 1992. Relationships with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke through 2008 were assessed.

RESULTS: During 30 829 person-years, 1625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After adjustment, higher plasma levels of ω3-PUFA biomarkers were associated with lower total mortality, with extreme-quintile hazard ratios of 0.83 for EPA (95% CI, 0.71 to 0.98; P for trend = 0.005), 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008), 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend < 0.001). Lower risk was largely attributable to fewer cardiovascular than noncardiovascular deaths. Individuals in the highest quintile of phospholipid ω3-PUFA level lived an average of 2.22 more years (CI, 0.75 to 3.13 years) after age 65 years than did those in the lowest quintile.

LIMITATION: Temporal changes in fatty acid levels and misclassification of causes of death may have resulted in underestimated associations, and unmeasured or imperfectly measured covariates may have caused residual confounding.

CONCLUSION: Higher circulating individual and total ω3-PUFA levels are associated with lower total mortality, especially CHD death, in older adults.

PRIMARY FUNDING SOURCE: National Institutes of Health.

%B Ann Intern Med %V 158 %P 515-25 %8 2013 Apr 02 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23546563?dopt=Abstract %R 10.7326/0003-4819-158-7-201304020-00003 %0 Journal Article %J Am J Cardiol %D 2013 %T Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study). %A van Ballegooijen, Adriana J %A Visser, Marjolein %A Kestenbaum, Bryan %A Siscovick, David S %A de Boer, Ian H %A Gottdiener, John S %A deFilippi, Christopher R %A Brouwer, Ingeborg A %K Adult %K Aged %K Biomarkers %K Cardiovascular Diseases %K Echocardiography %K Electrocardiography %K Female %K Follow-Up Studies %K Heart Ventricles %K Humans %K Incidence %K Male %K Mass Spectrometry %K Middle Aged %K Parathyroid Hormone %K Prospective Studies %K United States %K Vitamin D %X

Vitamin D and parathyroid hormone (PTH) may affect cardiovascular health in patients with kidney disease and in the general population. The aim of this study was to investigate associations of serum 25-hydroxyvitamin D (25(OH)D) and PTH concentrations with a comprehensive set of biochemical, electrocardiographic, and echocardiographic measurements of cardiac structure and function in the Cardiovascular Health Study. A total of 2,312 subjects who were free of cardiovascular disease at baseline were studied. Serum 25(OH)D and intact PTH concentrations were measured using mass spectrometry and a 2-site immunoassay. Outcomes were N-terminal pro-B-type natriuretic peptide, cardiac troponin T, electrocardiographic measures of conduction, and echocardiographic measures of left ventricular mass and diastolic dysfunction. At baseline, subjects had a mean age of 73.9 ± 4.9 years, 69.7% were women, and 21% had chronic kidney disease (glomerular filtration rate <60 ml/min). Mean 25(OH)D was 25.2 ± 10.2 ng/ml, and median PTH was 51 pg/ml (range 39 to 65). After adjustment, 25(OH)D was not associated with any of the biochemical, conduction, or echocardiographic outcomes. Serum PTH levels ≥65 pg/ml were associated with greater N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass in patients with chronic kidney disease. The regression coefficients were: 120 pg/ml (95% confidence interval 36.1 to 204), 5.2 pg/ml (95% confidence interval 3.0 to 7.4), and 17 g (95% confidence interval 6.2 to 27.8) (p <0.001). In subjects with normal kidney function, PTH was not associated with the outcomes. In conclusion, in older adults with chronic kidney disease, PTH excess is associated with higher N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass. These findings suggest a role for PTH in cardiovascular health and the prevention of cardiac diseases.

%B Am J Cardiol %V 111 %P 418-24 %8 2013 Feb 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23168286?dopt=Abstract %R 10.1016/j.amjcard.2012.10.021 %0 Journal Article %J Am J Epidemiol %D 2013 %T Risk factors for type 2 diabetes mellitus preceded by β-cell dysfunction, insulin resistance, or both in older adults: the Cardiovascular Health Study. %A Imamura, Fumiaki %A Mukamal, Kenneth J %A Meigs, James B %A Luchsinger, José A %A Ix, Joachim H %A Siscovick, David S %A Mozaffarian, Dariush %K Adiposity %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Alcohol Drinking %K Blood Pressure %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Incidence %K Insulin Resistance %K Insulin-Secreting Cells %K Lipids %K Male %K Prospective Studies %K Risk Factors %K Socioeconomic Factors %K United States %X

Insulin resistance (IR) and pancreatic β-cell dysfunction lead to type 2 diabetes mellitus (DM). We tested whether risk factors would differ for DM that was preceded predominantly by IR, β-cell dysfunction, or both among 4,384 older adults (mean age, 72.7 (standard deviation, 5.6) years) in the Cardiovascular Health Study, which was conducted in North Carolina, California, Maryland, and Pennsylvania (1989-2007). When evaluating established risk factors, we found older age, greater adiposity, higher systolic blood pressure, a lower high-density lipoprotein cholesterol level, a higher triglyceride level, and a lower alcohol intake to be independently associated with greater IR but, conversely, with better β-cell function (P < 0.001). The prospective associations between some risk factors and incident DM varied significantly depending on whether DM was preceded predominantly by IR, β-cell dysfunction, or both. For example, obesity and lower high-density lipoprotein cholesterol levels were positively associated with DM preceded predominantly by IR (hazard ratio (HR) = 5.02, 95% confidence interval (CI): 2.81, 9.00; and HR = 1.97, 95% CI: 1.32, 2.93, respectively), with a significant association with and an insignificant trend toward a lower risk of DM preceded predominantly by β-cell dysfunction (HR = 0.33, 95% CI: 0.14, 0.80; and HR = 0.78, 95% CI: 0.43, 1.39, respectively). In conclusion, among older adults, DM risk factors were differentially associated with DM preceded predominantly by IR or β-cell dysfunction. Biologic and clinical implications of putative subtypes of DM require further investigation.

%B Am J Epidemiol %V 177 %P 1418-29 %8 2013 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23707958?dopt=Abstract %& 1418 %R 10.1093/aje/kws440 %0 Journal Article %J J Clin Endocrinol Metab %D 2013 %T Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults. %A Kizer, Jorge R %A Benkeser, David %A Arnold, Alice M %A Djoussé, Luc %A Zieman, Susan J %A Mukamal, Kenneth J %A Tracy, Russell P %A Mantzoros, Christos S %A Siscovick, David S %A Gottdiener, John S %A Ix, Joachim H %K Adiponectin %K Adult %K Aged %K Aged, 80 and over %K Brain Ischemia %K Cardiovascular Diseases %K Case-Control Studies %K Cohort Studies %K Coronary Disease %K Female %K Humans %K Male %K Molecular Weight %K Residence Characteristics %K Risk Factors %K Stroke %X

CONTEXT: Adiponectin is atheroprotective in the laboratory, but prospective studies have shown opposite associations with cardiovascular disease (CVD) in healthy middle-aged populations (protective) and older cohorts (adverse). Whether this relates to different proportions of high-molecular-weight (HMW) adiponectin is unknown.

OBJECTIVE: The aim of the study was to test the hypothesis that total adiponectin is directly associated, but HMW adiponectin is inversely related, with CVD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: We evaluated 3290 participants free of prevalent CVD in a longitudinal cohort study of U.S. adults aged 65 yr and older.

MAIN OUTCOME MEASURES: We measured incident CVD (n = 1291), comprising coronary heart disease and ischemic stroke.

RESULTS: Total and HMW adiponectin were tightly correlated (r = 0.94). Cubic splines adjusted for potential confounders revealed that the associations of total and HMW adiponectin with CVD were U-shaped, with inflection points of 20 and 10 mg/liter, respectively. After controlling for potential confounding, levels of total and HMW adiponectin below these cutpoints tended to be inversely associated with incident CVD, driven by their significant or near-significant relations with coronary heart disease [hazard ratio (HR), 0.85 per sd increase; 95% confidence interval (CI), 0.75-96; and HR, 0.87; 95% CI, 0.75-1.01, respectively]. These associations were abrogated by additional inclusion of putative metabolic intermediates. Above these cutpoints, however, both total and HMW adiponectin were significantly directly associated with CVD after adjustment for confounders and, particularly, mediators (HR, 1.20 per sd increase; 95% CI, 1.06-1.35; and HR, 1.12; 95% CI, 1.02-1.24, respectively).

CONCLUSION: In community-living elders, total and HMW adiponectin showed similar U-shaped relationships with CVD. The inverse relation in the lower range, but not the direct association at the higher end, disappeared after inclusion of putative intermediates, suggesting that high levels may reflect adverse processes separate from adiponectin's beneficial glycometabolic properties.

%B J Clin Endocrinol Metab %V 98 %P 255-63 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23162097?dopt=Abstract %R 10.1210/jc.2012-2103 %0 Journal Article %J Atherosclerosis %D 2014 %T Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults. %A Kizer, Jorge R %A Benkeser, David %A Arnold, Alice M %A Ix, Joachim H %A Mukamal, Kenneth J %A Djoussé, Luc %A Tracy, Russell P %A Siscovick, David S %A Psaty, Bruce M %A Zieman, Susan J %K Aged %K Albumins %K Antihypertensive Agents %K Blood Pressure %K Cardiovascular Diseases %K Cohort Studies %K Coronary Disease %K Creatinine %K Female %K Glomerular Filtration Rate %K Glycation End Products, Advanced %K Humans %K Immunoassay %K Incidence %K Lysine %K Male %K Oxidative Stress %K Proportional Hazards Models %K Stroke %K Treatment Outcome %X

BACKGROUND: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress--such as diabetes, chronic kidney disease and aging--where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined.

METHODS: To test the hypothesis that circulating levels of N(ɛ)-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older.

RESULTS: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95% confidence interval [CI]=1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke.

CONCLUSIONS: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML's value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.

%B Atherosclerosis %V 235 %P 116-21 %8 2014 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24825341?dopt=Abstract %R 10.1016/j.atherosclerosis.2014.04.013 %0 Journal Article %J BMJ %D 2014 %T Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. %A Holmes, Michael V %A Dale, Caroline E %A Zuccolo, Luisa %A Silverwood, Richard J %A Guo, Yiran %A Ye, Zheng %A Prieto-Merino, David %A Dehghan, Abbas %A Trompet, Stella %A Wong, Andrew %A Cavadino, Alana %A Drogan, Dagmar %A Padmanabhan, Sandosh %A Li, Shanshan %A Yesupriya, Ajay %A Leusink, Maarten %A Sundström, Johan %A Hubacek, Jaroslav A %A Pikhart, Hynek %A Swerdlow, Daniel I %A Panayiotou, Andrie G %A Borinskaya, Svetlana A %A Finan, Chris %A Shah, Sonia %A Kuchenbaecker, Karoline B %A Shah, Tina %A Engmann, Jorgen %A Folkersen, Lasse %A Eriksson, Per %A Ricceri, Fulvio %A Melander, Olle %A Sacerdote, Carlotta %A Gamble, Dale M %A Rayaprolu, Sruti %A Ross, Owen A %A McLachlan, Stela %A Vikhireva, Olga %A Sluijs, Ivonne %A Scott, Robert A %A Adamkova, Vera %A Flicker, Leon %A Bockxmeer, Frank M van %A Power, Christine %A Marques-Vidal, Pedro %A Meade, Tom %A Marmot, Michael G %A Ferro, Jose M %A Paulos-Pinheiro, Sofia %A Humphries, Steve E %A Talmud, Philippa J %A Mateo Leach, Irene %A Verweij, Niek %A Linneberg, Allan %A Skaaby, Tea %A Doevendans, Pieter A %A Cramer, Maarten J %A van der Harst, Pim %A Klungel, Olaf H %A Dowling, Nicole F %A Dominiczak, Anna F %A Kumari, Meena %A Nicolaides, Andrew N %A Weikert, Cornelia %A Boeing, Heiner %A Ebrahim, Shah %A Gaunt, Tom R %A Price, Jackie F %A Lannfelt, Lars %A Peasey, Anne %A Kubinova, Ruzena %A Pajak, Andrzej %A Malyutina, Sofia %A Voevoda, Mikhail I %A Tamosiunas, Abdonas %A Maitland-van der Zee, Anke H %A Norman, Paul E %A Hankey, Graeme J %A Bergmann, Manuela M %A Hofman, Albert %A Franco, Oscar H %A Cooper, Jackie %A Palmen, Jutta %A Spiering, Wilko %A de Jong, Pim A %A Kuh, Diana %A Hardy, Rebecca %A Uitterlinden, André G %A Ikram, M Arfan %A Ford, Ian %A Hyppönen, Elina %A Almeida, Osvaldo P %A Wareham, Nicholas J %A Khaw, Kay-Tee %A Hamsten, Anders %A Husemoen, Lise Lotte N %A Tjønneland, Anne %A Tolstrup, Janne S %A Rimm, Eric %A Beulens, Joline W J %A Verschuren, W M Monique %A Onland-Moret, N Charlotte %A Hofker, Marten H %A Wannamethee, S Goya %A Whincup, Peter H %A Morris, Richard %A Vicente, Astrid M %A Watkins, Hugh %A Farrall, Martin %A Jukema, J Wouter %A Meschia, James %A Cupples, L Adrienne %A Sharp, Stephen J %A Fornage, Myriam %A Kooperberg, Charles %A LaCroix, Andrea Z %A Dai, James Y %A Lanktree, Matthew B %A Siscovick, David S %A Jorgenson, Eric %A Spring, Bonnie %A Coresh, Josef %A Li, Yun R %A Buxbaum, Sarah G %A Schreiner, Pamela J %A Ellison, R Curtis %A Tsai, Michael Y %A Patel, Sanjay R %A Redline, Susan %A Johnson, Andrew D %A Hoogeveen, Ron C %A Hakonarson, Hakon %A Rotter, Jerome I %A Boerwinkle, Eric %A de Bakker, Paul I W %A Kivimaki, Mika %A Asselbergs, Folkert W %A Sattar, Naveed %A Lawlor, Debbie A %A Whittaker, John %A Davey Smith, George %A Mukamal, Kenneth %A Psaty, Bruce M %A Wilson, James G %A Lange, Leslie A %A Hamidovic, Ajna %A Hingorani, Aroon D %A Nordestgaard, Børge G %A Bobak, Martin %A Leon, David A %A Langenberg, Claudia %A Palmer, Tom M %A Reiner, Alex P %A Keating, Brendan J %A Dudbridge, Frank %A Casas, Juan P %K Adult %K Aged %K Alcohol Dehydrogenase %K Alcohol Drinking %K Biomarkers %K Coronary Disease %K Female %K Genetic Markers %K Genotype %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Models, Statistical %K Polymorphism, Single Nucleotide %K Stroke %X

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

%B BMJ %V 349 %P g4164 %8 2014 Jul 10 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract %R 10.1136/bmj.g4164 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Cornes, Belinda K %A Brody, Jennifer A %A Nikpoor, Naghmeh %A Morrison, Alanna C %A Chu, Huan %A Ahn, Byung Soo %A Wang, Shuai %A Dauriz, Marco %A Barzilay, Joshua I %A Dupuis, Josée %A Florez, Jose C %A Coresh, Josef %A Gibbs, Richard A %A Kao, W H Linda %A Liu, Ching-Ti %A McKnight, Barbara %A Muzny, Donna %A Pankow, James S %A Reid, Jeffrey G %A White, Charles C %A Johnson, Andrew D %A Wong, Tien Y %A Psaty, Bruce M %A Boerwinkle, Eric %A Rotter, Jerome I %A Siscovick, David S %A Sladek, Robert %A Meigs, James B %K Aged %K Aged, 80 and over %K Aging %K Blood Glucose %K Chromosomes, Human, Pair 11 %K Cohort Studies %K Death Domain Receptor Signaling Adaptor Proteins %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Guanine Nucleotide Exchange Factors %K Heart Diseases %K Humans %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

%B Circ Cardiovasc Genet %V 7 %P 374-382 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000169 %0 Journal Article %J Am J Hum Genet %D 2014 %T Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. %A Peloso, Gina M %A Auer, Paul L %A Bis, Joshua C %A Voorman, Arend %A Morrison, Alanna C %A Stitziel, Nathan O %A Brody, Jennifer A %A Khetarpal, Sumeet A %A Crosby, Jacy R %A Fornage, Myriam %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Feitosa, Mary F %A Davies, Gail %A Huffman, Jennifer E %A Manichaikul, Ani %A Davis, Brian %A Lohman, Kurt %A Joon, Aron Y %A Smith, Albert V %A Grove, Megan L %A Zanoni, Paolo %A Redon, Valeska %A Demissie, Serkalem %A Lawson, Kim %A Peters, Ulrike %A Carlson, Christopher %A Jackson, Rebecca D %A Ryckman, Kelli K %A Mackey, Rachel H %A Robinson, Jennifer G %A Siscovick, David S %A Schreiner, Pamela J %A Mychaleckyj, Josyf C %A Pankow, James S %A Hofman, Albert %A Uitterlinden, André G %A Harris, Tamara B %A Taylor, Kent D %A Stafford, Jeanette M %A Reynolds, Lindsay M %A Marioni, Riccardo E %A Dehghan, Abbas %A Franco, Oscar H %A Patel, Aniruddh P %A Lu, Yingchang %A Hindy, George %A Gottesman, Omri %A Bottinger, Erwin P %A Melander, Olle %A Orho-Melander, Marju %A Loos, Ruth J F %A Duga, Stefano %A Merlini, Piera Angelica %A Farrall, Martin %A Goel, Anuj %A Asselta, Rosanna %A Girelli, Domenico %A Martinelli, Nicola %A Shah, Svati H %A Kraus, William E %A Li, Mingyao %A Rader, Daniel J %A Reilly, Muredach P %A McPherson, Ruth %A Watkins, Hugh %A Ardissino, Diego %A Zhang, Qunyuan %A Wang, Judy %A Tsai, Michael Y %A Taylor, Herman A %A Correa, Adolfo %A Griswold, Michael E %A Lange, Leslie A %A Starr, John M %A Rudan, Igor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Ordovas, Jose M %A Levy, Daniel %A Chen, Y-D Ida %A Reiner, Alexander P %A Hayward, Caroline %A Polasek, Ozren %A Deary, Ian J %A Borecki, Ingrid B %A Liu, Yongmei %A Gudnason, Vilmundur %A Wilson, James G %A van Duijn, Cornelia M %A Kooperberg, Charles %A Rich, Stephen S %A Psaty, Bruce M %A Rotter, Jerome I %A O'Donnell, Christopher J %A Rice, Kenneth %A Boerwinkle, Eric %A Kathiresan, Sekar %A Cupples, L Adrienne %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Adult %K African Continental Ancestry Group %K Aged %K Alleles %K Animals %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Coronary Disease %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Code %K Genetic Variation %K Humans %K Linear Models %K Male %K Mice %K Mice, Inbred C57BL %K Microtubule-Associated Proteins %K Middle Aged %K Phenotype %K Sequence Analysis, DNA %K Subtilisins %K Triglycerides %X

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.

%B Am J Hum Genet %V 94 %P 223-32 %8 2014 Feb 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract %R 10.1016/j.ajhg.2014.01.009 %0 Journal Article %J Am Heart J %D 2014 %T Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS). %A Rosenberg, Michael A %A Maziarz, Marlena %A Tan, Alex Y %A Glazer, Nicole L %A Zieman, Susan J %A Kizer, Jorge R %A Ix, Joachim H %A Djoussé, Luc %A Siscovick, David S %A Heckbert, Susan R %A Mukamal, Kenneth J %K Aged %K Atrial Fibrillation %K Biomarkers %K Cardiomyopathies %K Electrocardiography %K Enzyme-Linked Immunosorbent Assay %K Female %K Fibrosis %K Follow-Up Studies %K Humans %K Incidence %K Male %K Peptide Fragments %K Procollagen %K Prospective Studies %K Risk Factors %K Time Factors %K Transforming Growth Factor beta1 %K United States %X

BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited.

METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years.

RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk.

CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.

%B Am Heart J %V 167 %P 723-8.e2 %8 2014 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24766983?dopt=Abstract %R 10.1016/j.ahj.2014.01.010 %0 Journal Article %J J Bone Miner Res %D 2014 %T Circulating levels of carboxy‐methyl‐lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study. %A Barzilay, Joshua I %A Bůzková, Petra %A Zieman, Susan J %A Kizer, Jorge R %A Djoussé, Luc %A Ix, Joachim H %A Tracy, Russell P %A Siscovick, David S %A Cauley, Jane A %A Mukamal, Kenneth J %K Age Factors %K Aged %K Female %K Follow-Up Studies %K Glycation End Products, Advanced %K Hip Fractures %K Humans %K Incidence %K Lysine %K Male %K Prospective Studies %K Retrospective Studies %K Risk Factors %X

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy‐methyl‐lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68–102 years; 39.8% male) for a median of 9.22 years (range, 0.01–12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow‐up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant‐years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95% confidence interval [CI], 1.16–1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95% CI, 1.05–1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.

%B J Bone Miner Res %V 29 %P 1061-6 %8 2014 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24877243?dopt=Abstract %0 Journal Article %J Circulation %D 2014 %T Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study. %A Wu, Jason H Y %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Psaty, Bruce M %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Arachidonic Acid %K Biomarkers %K Cohort Studies %K Coronary Disease %K Fatty Acids, Omega-3 %K Fatty Acids, Omega-6 %K Fatty Acids, Unsaturated %K Female %K Follow-Up Studies %K Humans %K Linoleic Acid %K Male %K Prospective Studies %K Regression Analysis %K Risk Factors %K Stroke %K Survival Rate %K United States %X

BACKGROUND: Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.

METHODS AND RESULTS: Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.

CONCLUSIONS: High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

%B Circulation %V 130 %P 1245-53 %8 2014 Oct 7 %G eng %N 15 %1 http://www.ncbi.nlm.nih.gov/pubmed/25124495?dopt=Abstract %R 10.1161/CIRCULATIONAHA.114.011590 %0 Journal Article %J Heart Rhythm %D 2014 %T Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest. %A Lemaitre, Rozenn N %A Johnson, Catherine O %A Hesselson, Stephanie %A Sotoodehnia, Nona %A Sotoodhenia, Nona %A McKnight, Barbara %A Sitlani, Colleen M %A Rea, Thomas D %A King, Irena B %A Kwok, Pui-Yan %A Mak, Angel %A Li, Guo %A Brody, Jennifer %A Larson, Eric %A Mozaffarian, Dariush %A Psaty, Bruce M %A Huertas-Vazquez, Adriana %A Tardif, Jean-Claude %A Albert, Christine M %A Lyytikäinen, Leo-Pekka %A Arking, Dan E %A Kääb, Stefan %A Huikuri, Heikki V %A Krijthe, Bouwe P %A Eijgelsheim, Mark %A Wang, Ying A %A Reinier, Kyndaron %A Lehtimäki, Terho %A Pulit, Sara L %A Brugada, Ramon %A Müller-Nurasyid, Martina %A Newton-Cheh, Chris H %A Karhunen, Pekka J %A Stricker, Bruno H %A Goyette, Philippe %A Rotter, Jerome I %A Chugh, Sumeet S %A Chakravarti, Aravinda %A Jouven, Xavier %A Siscovick, David S %K 1-Acylglycerophosphocholine O-Acyltransferase %K Aged %K Algorithms %K Alleles %K Case-Control Studies %K Death, Sudden, Cardiac %K Fatty Acids %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Male %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).

OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.

METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.

RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase.

CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.

%B Heart Rhythm %V 11 %P 471-7 %8 2014 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24418166?dopt=Abstract %R 10.1016/j.hrthm.2014.01.008 %0 Journal Article %J Am J Hum Genet %D 2014 %T Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. %A Ganesh, Santhi K %A Chasman, Daniel I %A Larson, Martin G %A Guo, Xiuqing %A Verwoert, Germain %A Bis, Joshua C %A Gu, Xiangjun %A Smith, Albert V %A Yang, Min-Lee %A Zhang, Yan %A Ehret, Georg %A Rose, Lynda M %A Hwang, Shih-Jen %A Papanicolau, George J %A Sijbrands, Eric J %A Rice, Kenneth %A Eiriksdottir, Gudny %A Pihur, Vasyl %A Ridker, Paul M %A Vasan, Ramachandran S %A Newton-Cheh, Christopher %A Raffel, Leslie J %A Amin, Najaf %A Rotter, Jerome I %A Liu, Kiang %A Launer, Lenore J %A Xu, Ming %A Caulfield, Mark %A Morrison, Alanna C %A Johnson, Andrew D %A Vaidya, Dhananjay %A Dehghan, Abbas %A Li, Guo %A Bouchard, Claude %A Harris, Tamara B %A Zhang, He %A Boerwinkle, Eric %A Siscovick, David S %A Gao, Wei %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A Willer, Cristen J %A Franco, Oscar H %A Huo, Yong %A Witteman, Jacqueline C M %A Munroe, Patricia B %A Gudnason, Vilmundur %A Palmas, Walter %A van Duijn, Cornelia %A Fornage, Myriam %A Levy, Daniel %A Psaty, Bruce M %A Chakravarti, Aravinda %K Blood Pressure %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

%B Am J Hum Genet %V 95 %P 49-65 %8 2014 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract %R 10.1016/j.ajhg.2014.06.002 %0 Journal Article %J Am J Kidney Dis %D 2014 %T Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. %A de Boer, Ian H %A Sachs, Michael C %A Chonchol, Michel %A Himmelfarb, Jonathan %A Hoofnagle, Andrew N %A Ix, Joachim H %A Kremsdorf, Robin A %A Lin, Yvonne S %A Mehrotra, Rajnish %A Robinson-Cohen, Cassianne %A Siscovick, David S %A Steffes, Michael W %A Thummel, Kenneth E %A Tracy, Russell P %A Wang, Zhican %A Kestenbaum, Bryan %K 24,25-Dihydroxyvitamin D 3 %K Adult %K Aged %K Aged, 80 and over %K Biomarkers %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Observational Studies as Topic %K Randomized Controlled Trials as Topic %K Young Adult %X

BACKGROUND: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.

STUDY DESIGN: Cross-sectional study.

SETTING & PARTICIPANTS: 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).

PREDICTOR: eGFR.

OUTCOME: Circulating 24,25(OH)2D3 concentration.

MEASUREMENTS: GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.

RESULTS: Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.

LIMITATIONS: Lack of direct pharmacokinetic measurements of vitamin D catabolism.

CONCLUSIONS: Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.

%B Am J Kidney Dis %V 64 %P 187-97 %8 2014 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24703961?dopt=Abstract %R 10.1053/j.ajkd.2014.02.015 %0 Journal Article %J Atherosclerosis %D 2014 %T Fibroblast growth factor 23, the ankle-brachial index, and incident peripheral artery disease in the Cardiovascular Health Study. %A Garimella, Pranav S %A Ix, Joachim H %A Katz, Ronit %A Chonchol, Michel B %A Kestenbaum, Bryan R %A de Boer, Ian H %A Siscovick, David S %A Shastri, Shani %A Hiramoto, Jade S %A Shlipak, Michael G %A Sarnak, Mark J %K Aged %K Ankle Brachial Index %K Cardiovascular Diseases %K Cross-Sectional Studies %K Fibroblast Growth Factors %K Humans %K Incidence %K Peripheral Arterial Disease %K Risk Factors %X

BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.

METHODS: Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.

RESULTS: The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1-1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76-1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75-1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28-3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79-2.70).

CONCLUSIONS: In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.

%B Atherosclerosis %V 233 %P 91-6 %8 2014 Mar %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24529128?dopt=Abstract %R 10.1016/j.atherosclerosis.2013.12.015 %0 Journal Article %J Circulation %D 2014 %T Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). %A Mathew, Jehu S %A Sachs, Michael C %A Katz, Ronit %A Patton, Kristen K %A Heckbert, Susan R %A Hoofnagle, Andrew N %A Alonso, Alvaro %A Chonchol, Michel %A Deo, Rajat %A Ix, Joachim H %A Siscovick, David S %A Kestenbaum, Bryan %A de Boer, Ian H %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Comorbidity %K Ethnic Groups %K Female %K Fibroblast Growth Factor 3 %K Follow-Up Studies %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Hypertrophy, Left Ventricular %K Male %K Middle Aged %K Phosphates %K Proportional Hazards Models %K Renal Insufficiency, Chronic %K Risk Factors %K United States %K Ventricular Dysfunction, Left %K Ventricular Remodeling %K Vitamin D %X

BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.

METHODS AND RESULTS: We tested the associations of circulating FGF-23 concentration with incident AF among 6398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over a median of 7.7 and 8.0 years of follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each 2-fold-higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (hazard ratio, 1.41; 95% confidence interval, 1.13-1.76; P=0.003) and a 30% higher risk of incident AF in CHS (hazard ratio, 1.30; 95% confidence interval, 1.05-1.61; P=0.016) after adjustment for potential confounding characteristics, including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (hazard ratio, 1.15 per 0.5 mg/dL; 95% confidence interval, 1.02-1.31; P=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjustment for FGF-23.

CONCLUSION: Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.

%B Circulation %V 130 %P 298-307 %8 2014 Jul 22 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24920722?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.005499 %0 Journal Article %J Clin J Am Soc Nephrol %D 2014 %T Fibroblast growth factor-23 and the long-term risk of hospital-associated AKI among community-dwelling older individuals. %A Brown, Jeremiah R %A Katz, Ronit %A Ix, Joachim H %A de Boer, Ian H %A Siscovick, David S %A Grams, Morgan E %A Shlipak, Michael %A Sarnak, Mark J %K Acute Kidney Injury %K Age Factors %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Creatinine %K Cystatin C %K Female %K Fibroblast Growth Factors %K Glomerular Filtration Rate %K Hospitalization %K Humans %K Independent Living %K Kidney %K Longitudinal Studies %K Male %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Time Factors %X

BACKGROUND AND OBJECTIVES: AKI occurs frequently in older persons. Elevated circulating fibroblast growth factor-23 (FGF-23), a known marker of impaired mineral metabolism, may also reflect tubular dysfunction and risk of AKI. This study evaluated FGF-23 as well as traditional markers of kidney disease, namely urine albumin-to-creatinine ratio (UACR) and creatinine-cystatin C estimated GFR (eGFRCrCyC), as risk factors for AKI in elderly individuals.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma FGF-23, UACR, and eGFRCrCyC were measured in 3241 community-dwelling elderly individuals in the Cardiovascular Health Study. Hospitalization for AKI was defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Associations of each biomarker with AKI were evaluated using Cox proportional hazards models adjusted for demographics, cardiovascular risk factors, and biomarkers of kidney function.

RESULTS: The mean participant age was 78 years; 60% of participants were women and 16% were African American. The median (interquartile range) values of biomarkers were as follows: FGF-23, 70 RU/ml (53, 99); UACR, 8.88 mg/g (4.71, 20.47); and eGFRCrCyC, 71 ml/min per 1.73 m(2) (59, 83). Hospitalized AKI occurred in 119 participants over 10.0 years of median follow-up. In fully adjusted analyses, compared with the lowest quartiles, the highest quartiles of FGF-23 (≥100 RU/ml) and UACR (≥20.9 mg/g) were associated with AKI (FGF-23: hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.04 to 3.80; and UACR: HR, 3.35; 95% CI, 1.83 to 6.13). Compared with the highest quartile, the lowest quartile of eGFRCrCyC (<57 ml/min per 1.73 m(2)) was associated with AKI with an HR of 2.15 (95% CI, 1.21 to 3.82).

CONCLUSIONS: FGF-23 adjusted for albuminuria, cardiovascular disease risk factors, and baseline eGFR is independently associated with a higher risk of AKI hospitalizations in community-dwelling elderly individuals. Further studies to understand the nature of this association are warranted.

%B Clin J Am Soc Nephrol %V 9 %P 239-46 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24262510?dopt=Abstract %R 10.2215/CJN.05830513 %0 Journal Article %J Am J Epidemiol %D 2014 %T Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study. %A Agarwal, Isha %A Glazer, Nicole L %A Barasch, Eddy %A Biggs, Mary L %A Djoussé, Luc %A Fitzpatrick, Annette L %A Gottdiener, John S %A Ix, Joachim H %A Kizer, Jorge R %A Rimm, Eric B %A Siscovick, David S %A Tracy, Russell P %A Zieman, Susan J %A Mukamal, Kenneth J %K Aged %K Aged, 80 and over %K Biomarkers %K Cause of Death %K Female %K Fibrosis %K Follow-Up Studies %K Humans %K Likelihood Functions %K Male %K Multivariate Analysis %K Peptide Fragments %K Procollagen %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Transforming Growth Factor beta %X

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

%B Am J Epidemiol %V 179 %P 1331-9 %8 2014 Jun 01 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24771724?dopt=Abstract %R 10.1093/aje/kwu067 %0 Journal Article %J Hum Mol Genet %D 2014 %T FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. %A Qi, Qibin %A Kilpeläinen, Tuomas O %A Downer, Mary K %A Tanaka, Toshiko %A Smith, Caren E %A Sluijs, Ivonne %A Sonestedt, Emily %A Chu, Audrey Y %A Renstrom, Frida %A Lin, Xiaochen %A Ängquist, Lars H %A Huang, Jinyan %A Liu, Zhonghua %A Li, Yanping %A Asif Ali, Muhammad %A Xu, Min %A Ahluwalia, Tarunveer Singh %A Boer, Jolanda M A %A Chen, Peng %A Daimon, Makoto %A Eriksson, Johan %A Perola, Markus %A Friedlander, Yechiel %A Gao, Yu-Tang %A Heppe, Denise H M %A Holloway, John W %A Houston, Denise K %A Kanoni, Stavroula %A Kim, Yu-Mi %A Laaksonen, Maarit A %A Jääskeläinen, Tiina %A Lee, Nanette R %A Lehtimäki, Terho %A Lemaitre, Rozenn N %A Lu, Wei %A Luben, Robert N %A Manichaikul, Ani %A Männistö, Satu %A Marques-Vidal, Pedro %A Monda, Keri L %A Ngwa, Julius S %A Perusse, Louis %A van Rooij, Frank J A %A Xiang, Yong-Bing %A Wen, Wanqing %A Wojczynski, Mary K %A Zhu, Jingwen %A Borecki, Ingrid B %A Bouchard, Claude %A Cai, Qiuyin %A Cooper, Cyrus %A Dedoussis, George V %A Deloukas, Panos %A Ferrucci, Luigi %A Forouhi, Nita G %A Hansen, Torben %A Christiansen, Lene %A Hofman, Albert %A Johansson, Ingegerd %A Jørgensen, Torben %A Karasawa, Shigeru %A Khaw, Kay-Tee %A Kim, Mi-Kyung %A Kristiansson, Kati %A Li, Huaixing %A Lin, Xu %A Liu, Yongmei %A Lohman, Kurt K %A Long, Jirong %A Mikkilä, Vera %A Mozaffarian, Dariush %A North, Kari %A Pedersen, Oluf %A Raitakari, Olli %A Rissanen, Harri %A Tuomilehto, Jaakko %A van der Schouw, Yvonne T %A Uitterlinden, André G %A Zillikens, M Carola %A Franco, Oscar H %A Shyong Tai, E %A Ou Shu, Xiao %A Siscovick, David S %A Toft, Ulla %A Verschuren, W M Monique %A Vollenweider, Peter %A Wareham, Nicholas J %A Witteman, Jacqueline C M %A Zheng, Wei %A Ridker, Paul M %A Kang, Jae H %A Liang, Liming %A Jensen, Majken K %A Curhan, Gary C %A Pasquale, Louis R %A Hunter, David J %A Mohlke, Karen L %A Uusitupa, Matti %A Cupples, L Adrienne %A Rankinen, Tuomo %A Orho-Melander, Marju %A Wang, Tao %A Chasman, Daniel I %A Franks, Paul W %A Sørensen, Thorkild I A %A Hu, Frank B %A Loos, Ruth J F %A Nettleton, Jennifer A %A Qi, Lu %K Adult %K African Americans %K Aged %K Alleles %K Asian Continental Ancestry Group %K Body Mass Index %K Dietary Carbohydrates %K Dietary Fats %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Female %K Gene Frequency %K Humans %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Proteins %X

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.

%B Hum Mol Genet %V 23 %P 6961-72 %8 2014 Dec 20 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/25104851?dopt=Abstract %R 10.1093/hmg/ddu411 %0 Journal Article %J Am J Hum Genet %D 2014 %T Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. %A Simino, Jeannette %A Shi, Gang %A Bis, Joshua C %A Chasman, Daniel I %A Ehret, Georg B %A Gu, Xiangjun %A Guo, Xiuqing %A Hwang, Shih-Jen %A Sijbrands, Eric %A Smith, Albert V %A Verwoert, Germaine C %A Bragg-Gresham, Jennifer L %A Cadby, Gemma %A Chen, Peng %A Cheng, Ching-Yu %A Corre, Tanguy %A de Boer, Rudolf A %A Goel, Anuj %A Johnson, Toby %A Khor, Chiea-Chuen %A Lluís-Ganella, Carla %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Sim, Xueling %A Sõber, Siim %A van der Most, Peter J %A Verweij, Niek %A Zhao, Jing Hua %A Amin, Najaf %A Boerwinkle, Eric %A Bouchard, Claude %A Dehghan, Abbas %A Eiriksdottir, Gudny %A Elosua, Roberto %A Franco, Oscar H %A Gieger, Christian %A Harris, Tamara B %A Hercberg, Serge %A Hofman, Albert %A James, Alan L %A Johnson, Andrew D %A Kähönen, Mika %A Khaw, Kay-Tee %A Kutalik, Zoltán %A Larson, Martin G %A Launer, Lenore J %A Li, Guo %A Liu, Jianjun %A Liu, Kiang %A Morrison, Alanna C %A Navis, Gerjan %A Ong, Rick Twee-Hee %A Papanicolau, George J %A Penninx, Brenda W %A Psaty, Bruce M %A Raffel, Leslie J %A Raitakari, Olli T %A Rice, Kenneth %A Rivadeneira, Fernando %A Rose, Lynda M %A Sanna, Serena %A Scott, Robert A %A Siscovick, David S %A Stolk, Ronald P %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Klauw, Melanie M %A Vasan, Ramachandran S %A Vithana, Eranga Nishanthie %A Völker, Uwe %A Völzke, Henry %A Watkins, Hugh %A Young, Terri L %A Aung, Tin %A Bochud, Murielle %A Farrall, Martin %A Hartman, Catharina A %A Laan, Maris %A Lakatta, Edward G %A Lehtimäki, Terho %A Loos, Ruth J F %A Lucas, Gavin %A Meneton, Pierre %A Palmer, Lyle J %A Rettig, Rainer %A Snieder, Harold %A Tai, E Shyong %A Teo, Yik-Ying %A van der Harst, Pim %A Wareham, Nicholas J %A Wijmenga, Cisca %A Wong, Tien Yin %A Fornage, Myriam %A Gudnason, Vilmundur %A Levy, Daniel %A Palmas, Walter %A Ridker, Paul M %A Rotter, Jerome I %A van Duijn, Cornelia M %A Witteman, Jacqueline C M %A Chakravarti, Aravinda %A Rao, Dabeeru C %K Adolescent %K Adult %K Age Factors %K Aged %K Blood Pressure %K Cohort Studies %K Humans %K Middle Aged %K Young Adult %X

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

%B Am J Hum Genet %V 95 %P 24-38 %8 2014 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24954895?dopt=Abstract %R 10.1016/j.ajhg.2014.05.010 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A D'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orrù, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %0 Journal Article %J Am J Epidemiol %D 2014 %T Genetic variants related to height and risk of atrial fibrillation: the cardiovascular health study. %A Rosenberg, Michael A %A Kaplan, Robert C %A Siscovick, David S %A Psaty, Bruce M %A Heckbert, Susan R %A Newton-Cheh, Christopher %A Mukamal, Kenneth J %K African Americans %K Aged %K Atrial Fibrillation %K Body Height %K Endonucleases %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Humans %K Longitudinal Studies %K Male %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Risk Factors %X

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.

%B Am J Epidemiol %V 180 %P 215-22 %8 2014 Jul 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24944287?dopt=Abstract %R 10.1093/aje/kwu126 %0 Journal Article %J Ann Epidemiol %D 2014 %T Height and risk of sudden cardiac death: the Atherosclerosis Risk in Communities and Cardiovascular Health studies. %A Rosenberg, Michael A %A Lopez, Faye L %A Bůzková, Petra %A Adabag, Selcuk %A Chen, Lin Y %A Sotoodehnia, Nona %A Kronmal, Richard A %A Siscovick, David S %A Alonso, Alvaro %A Buxton, Alfred %A Folsom, Aaron R %A Mukamal, Kenneth J %K Adult %K Aged %K Atherosclerosis %K Body Height %K Coronary Disease %K Death, Sudden, Cardiac %K Female %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Population Surveillance %K Prospective Studies %K Risk Factors %X

PURPOSE: Sudden cardiac death (SCD) is an important cause of mortality in the adult population. Height has been associated with cardiac hypertrophy and an increased risk of arrhythmias but also with decreased risk of coronary heart disease, suggesting a complex association with SCD.

METHODS: We examined the association of adult height with the risk of physician-adjudicated SCD in two large population-based cohorts: the Cardiovascular Health Study and the Atherosclerosis Risk in Communities study.

RESULTS: Over an average follow-up time of 11.7 years in Cardiovascular Health Study, there were 199 (3.6%) cases of SCD among 5556 participants. In Atherosclerosis Risk in Communities study, over 12.6 years, there were 227 (1.5%) cases of SCD among 15,633 participants. In both cohorts, there was a trend toward decreased SCD with taller height. In fixed effects meta-analysis, the pooled hazard ratio per 10 cm of height was 0.84; 95% confidence interval, 0.73-0.98; P = .03. The association of increased height with lower risk of SCD was slightly attenuated after inclusion of risk factors associated with height, such as hypertension and left ventricular hypertrophy. The association appeared stronger among men than women in both cohorts.

CONCLUSIONS: In two population-based prospective cohorts of different ages, greater height was associated with lower risk of SCD.

%B Ann Epidemiol %V 24 %P 174-179.e2 %8 2014 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24360853?dopt=Abstract %R 10.1016/j.annepidem.2013.11.008 %0 Journal Article %J J Diabetes Complications %D 2014 %T The influence of sex on cardiovascular outcomes associated with diabetes among older black and white adults. %A Vimalananda, Varsha G %A Biggs, Mary L %A Rosenzweig, James L %A Carnethon, Mercedes R %A Meigs, James B %A Thacker, Evan L %A Siscovick, David S %A Mukamal, Kenneth J %K African Continental Ancestry Group %K Age Factors %K Aged %K Aged, 80 and over %K Cohort Studies %K Coronary Disease %K Diabetes Complications %K European Continental Ancestry Group %K Female %K Heart Failure %K Humans %K Incidence %K Longitudinal Studies %K Male %K Prospective Studies %K Regression Analysis %K Retrospective Studies %K Risk Factors %K Sex Factors %K Survival Rate %X

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.

%B J Diabetes Complications %V 28 %P 316-22 %8 2014 May-Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24461547?dopt=Abstract %R 10.1016/j.jdiacomp.2013.12.004 %0 Journal Article %J PLoS Genet %D 2014 %T Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. %A Ng, Maggie C Y %A Shriner, Daniel %A Chen, Brian H %A Li, Jiang %A Chen, Wei-Min %A Guo, Xiuqing %A Liu, Jiankang %A Bielinski, Suzette J %A Yanek, Lisa R %A Nalls, Michael A %A Comeau, Mary E %A Rasmussen-Torvik, Laura J %A Jensen, Richard A %A Evans, Daniel S %A Sun, Yan V %A An, Ping %A Patel, Sanjay R %A Lu, Yingchang %A Long, Jirong %A Armstrong, Loren L %A Wagenknecht, Lynne %A Yang, Lingyao %A Snively, Beverly M %A Palmer, Nicholette D %A Mudgal, Poorva %A Langefeld, Carl D %A Keene, Keith L %A Freedman, Barry I %A Mychaleckyj, Josyf C %A Nayak, Uma %A Raffel, Leslie J %A Goodarzi, Mark O %A Chen, Y-D Ida %A Taylor, Herman A %A Correa, Adolfo %A Sims, Mario %A Couper, David %A Pankow, James S %A Boerwinkle, Eric %A Adeyemo, Adebowale %A Doumatey, Ayo %A Chen, Guanjie %A Mathias, Rasika A %A Vaidya, Dhananjay %A Singleton, Andrew B %A Zonderman, Alan B %A Igo, Robert P %A Sedor, John R %A Kabagambe, Edmond K %A Siscovick, David S %A McKnight, Barbara %A Rice, Kenneth %A Liu, Yongmei %A Hsueh, Wen-Chi %A Zhao, Wei %A Bielak, Lawrence F %A Kraja, Aldi %A Province, Michael A %A Bottinger, Erwin P %A Gottesman, Omri %A Cai, Qiuyin %A Zheng, Wei %A Blot, William J %A Lowe, William L %A Pacheco, Jennifer A %A Crawford, Dana C %A Grundberg, Elin %A Rich, Stephen S %A Hayes, M Geoffrey %A Shu, Xiao-Ou %A Loos, Ruth J F %A Borecki, Ingrid B %A Peyser, Patricia A %A Cummings, Steven R %A Psaty, Bruce M %A Fornage, Myriam %A Iyengar, Sudha K %A Evans, Michele K %A Becker, Diane M %A Kao, W H Linda %A Wilson, James G %A Rotter, Jerome I %A Sale, Michèle M %A Liu, Simin %A Rotimi, Charles N %A Bowden, Donald W %K African Americans %K Diabetes Mellitus, Type 2 %K Genome-Wide Association Study %K HLA-B27 Antigen %K HMGA2 Protein %K Humans %K KCNQ1 Potassium Channel %K Mutant Chimeric Proteins %K Polymorphism, Single Nucleotide %K Transcription Factor 7-Like 2 Protein %X

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94) %B PLoS Genet %V 10 %P e1004517 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25102180?dopt=Abstract %R 10.1371/journal.pgen.1004517 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Boerwinkle, Eric %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J Circulation %D 2014 %T Physical activity and heart rate variability in older adults: the Cardiovascular Health Study. %A Soares-Miranda, Luisa %A Sattelmair, Jacob %A Chaves, Paulo %A Duncan, Glen E %A Siscovick, David S %A Stein, Phyllis K %A Mozaffarian, Dariush %K Aged %K Cardiovascular Diseases %K Cross-Sectional Studies %K Electrocardiography, Ambulatory %K Female %K Follow-Up Studies %K Health Status %K Heart Rate %K Humans %K Leisure Activities %K Longitudinal Studies %K Male %K Motor Activity %K Prospective Studies %K Walking %X

BACKGROUND: Cardiac mortality and electrophysiological dysfunction both increase with age. Heart rate variability (HRV) provides indices of autonomic function and electrophysiology that are associated with cardiac risk. How habitual physical activity among older adults prospectively relates to HRV, including nonlinear indices of erratic sinus patterns, is not established. We hypothesized that increasing the levels of both total leisure-time activity and walking would be prospectively associated with more favorable time-domain, frequency-domain, and nonlinear HRV measures in older adults.

METHODS AND RESULTS: We evaluated serial longitudinal measures of both physical activity and 24-hour Holter HRV over 5 years among 985 older US adults in the community-based Cardiovascular Health Study. After multivariable adjustment, greater total leisure-time activity, walking distance, and walking pace were each prospectively associated with specific, more favorable HRV indices, including higher 24-hour standard deviation of all normal-to-normal intervals (Ptrend=0.009, 0.02, 0.06, respectively) and ultralow-frequency power (Ptrend=0.02, 0.008, 0.16, respectively). Greater walking pace was also associated with a higher short-term fractal scaling exponent (Ptrend=0.003) and lower Poincaré ratio (Ptrend=0.02), markers of less erratic sinus patterns.

CONCLUSIONS: Greater total leisure-time activity, and walking alone, as well, were prospectively associated with more favorable and specific indices of autonomic function in older adults, including several suggestive of more normal circadian fluctuations and less erratic sinoatrial firing. Our results suggest potential mechanisms that might contribute to lower cardiovascular mortality with habitual physical activity later in life.

%B Circulation %V 129 %P 2100-10 %8 2014 May 27 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/24799513?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.005361 %0 Journal Article %J Int J Stroke %D 2014 %T Plasma free fatty acids and risk of stroke in the Cardiovascular Health Study. %A Khawaja, Owais %A Maziarz, Marlena %A Biggs, Mary L %A Longstreth, William T %A Ix, Joachim H %A Kizer, Jorge R %A Zieman, Susan %A Tracy, Russell P %A Mozaffarian, Dariush %A Mukamal, Kenneth J %A Siscovick, David S %A Djoussé, Luc %K Aged %K Biomarkers %K Brain Ischemia %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Male %K Prospective Studies %K Risk %K Stroke %X

BACKGROUND: Although free fatty acids have been positively associated with risk factors for stroke, the role of plasma free fatty acids in the development of stroke has not been elucidated in older adults.

AIMS: We sought to examine the association between plasma free fatty acids and incident stroke.

METHODS: Prospective cohort of 4369 men and women≥65 years of age in the Cardiovascular Health Study. Plasma levels of free fatty acids were measured at the 1992-1993 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with free fatty acids concentrations.

RESULTS: The average age among participants was 75±5·2 years. During a median follow-up of 11·4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14·5, 14·9, and 17·6 per 1000 person-years across increasing tertiles of plasma free fatty acids. The adjusted hazard ratio (95% confidence interval) for incident stroke was 1·05 (0·97-1·14) per standard deviation increase in plasma free fatty acids. Restriction to ischemic stroke did not alter the results [hazard ratio (95% confidence interval): 1·04 (0·96-1·14) per standard deviation higher free fatty acids], and there was no effect modification by adiposity (P interaction=0·18) or by diabetes (P interaction=0·15).

CONCLUSION: Our data did not show an association of plasma free fatty acids with incident stroke among community dwelling older adults.

%B Int J Stroke %V 9 %P 917-20 %8 2014 Oct %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24447493?dopt=Abstract %R 10.1111/ijs.12216 %0 Journal Article %J Br J Nutr %D 2014 %T Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study. %A Fretts, Amanda M %A Mozaffarian, Dariush %A Siscovick, David S %A Sitlani, Colleen %A Psaty, Bruce M %A Rimm, Eric B %A Song, Xiaoling %A McKnight, Barbara %A Spiegelman, Donna %A King, Irena B %A Lemaitre, Rozenn N %K Aged %K alpha-Linolenic Acid %K Cardiovascular Diseases %K Cohort Studies %K Coronary Disease %K Diet %K Female %K Humans %K Male %K Mortality %K Phospholipids %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Stroke %K United States %X

Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18 : 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥ 65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.

%B Br J Nutr %V 112 %P 1206-13 %8 2014 Oct 14 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25159901?dopt=Abstract %R 10.1017/S0007114514001925 %0 Journal Article %J J Am Heart Assoc %D 2014 %T Plasma phospholipid saturated fatty acids and incident atrial fibrillation: the Cardiovascular Health Study. %A Fretts, Amanda M %A Mozaffarian, Dariush %A Siscovick, David S %A Djoussé, Luc %A Heckbert, Susan R %A King, Irena B %A McKnight, Barbara %A Sitlani, Colleen %A Sacks, Frank M %A Song, Xiaoling %A Sotoodehnia, Nona %A Spiegelman, Donna %A Wallace, Erin R %A Lemaitre, Rozenn N %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Eicosanoic Acids %K Fatty Acids %K Female %K Humans %K Longitudinal Studies %K Male %K Palmitic Acid %K Phospholipids %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Stearic Acids %K United States %X

BACKGROUND: Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF.

METHODS AND RESULTS: The study population included 2899 participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long-chain saturated fatty acids-palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)-with incident AF. During a median of 11.2 years of follow-up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95% CI) for AF in the top and bottom quartiles were 0.76 (95% CI: 0.61, 0.95) for 18:0; 0.78 (95% CI: 0.63, 0.97) for 20:0; 0.62 (95% CI: 0.50, 0.78) for 22:0; and 0.68 (95% CI: 0.55, 0.85) for 24:0.

CONCLUSIONS: Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer-chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.

%B J Am Heart Assoc %V 3 %P e000889 %8 2014 Jun 26 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24970268?dopt=Abstract %R 10.1161/JAHA.114.000889 %0 Journal Article %J Am J Cardiol %D 2014 %T Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study). %A Miedema, Michael D %A Maziarz, Marlena %A Biggs, Mary L %A Zieman, Susan J %A Kizer, Jorge R %A Ix, Joachim H %A Mozaffarian, Dariush %A Tracy, Russell P %A Psaty, Bruce M %A Siscovick, David S %A Mukamal, Kenneth J %A Djoussé, Luc %K Age Distribution %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Cardiovascular Diseases %K Cause of Death %K Fatty Acid-Binding Proteins %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Health Status %K Humans %K Male %K Prognosis %K Prospective Studies %K Risk Assessment %K Risk Factors %K Survival Rate %K Time Factors %K United States %X

Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95% CI 1.08 to 1.26 for men; HR 1.02, 95% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.

%B Am J Cardiol %V 114 %P 843-8 %8 2014 Sep 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25073566?dopt=Abstract %R 10.1016/j.amjcard.2014.06.012 %0 Journal Article %J Am J Cardiol %D 2014 %T Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults ≥65 years of age (from the Cardiovascular Health study). %A Karas, Maria G %A Benkeser, David %A Arnold, Alice M %A Bartz, Traci M %A Djoussé, Luc %A Mukamal, Kenneth J %A Ix, Joachim H %A Zieman, Susan J %A Siscovick, David S %A Tracy, Russell P %A Mantzoros, Christos S %A Gottdiener, John S %A deFilippi, Christopher R %A Kizer, Jorge R %K Adiponectin %K Age of Onset %K Aged %K Biomarkers %K Cross-Sectional Studies %K Echocardiography, Doppler %K Enzyme-Linked Immunosorbent Assay %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Prognosis %K Prospective Studies %K Recurrence %K Severity of Illness Index %K United States %K Ventricular Function, Left %X

Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine's association with new-onset HF remains less well defined. The aim of this study was to investigate the associations of total and high-molecular weight (HMW) adiponectin with incident HF (n = 780) and, in a subset, echocardiographic parameters in a community-based cohort of adults aged ≥65 years. Total and HMW adiponectin were measured in 3,228 subjects without prevalent HF, atrial fibrillation or CVD. The relations of total and HMW adiponectin with HF were nonlinear, with significant associations observed only for concentrations greater than the median (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios per SD increment in total adiponectin were 0.93 (95% confidence interval 0.72 to 1.21) for concentrations less than the median and 1.25 (95% confidence interval 1.14 to 1.38) higher than the median. There was a suggestion of effect modification by body mass index, whereby the association appeared strongest in participants with lower body mass indexes. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relations with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults.

%B Am J Cardiol %V 113 %P 328-34 %8 2014 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24169012?dopt=Abstract %R 10.1016/j.amjcard.2013.09.027 %0 Journal Article %J J Environ Public Health %D 2014 %T Residential relocation by older adults in response to incident cardiovascular health events: a case-crossover analysis. %A Lovasi, Gina S %A Richardson, John M %A Rodriguez, Carlos J %A Kop, Willem J %A Ahmed, Ali %A Brown, Arleen F %A Greenlee, Heather %A Siscovick, David S %K Aged %K Cardiovascular Diseases %K Cross-Over Studies %K Female %K Humans %K Incidence %K Life Change Events %K Logistic Models %K Longitudinal Studies %K Male %K Prospective Studies %K Residence Characteristics %K United States %X

OBJECTIVE: We use a case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new home address.

METHODS: We conducted an ambidirectional case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new address using data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study of 5,888 older adults from four U.S. sites beginning in 1989. Relocation was assessed twice a year during follow-up. Event occurrences were classified as present or absent for the period preceding the first reported move, as compared with an equal length of time immediately prior to and following this period.

RESULTS: Older adults (65+) that experience incident cardiovascular disease had an increased probability of reporting a change of residence during the following year (OR 1.6, 95% confidence interval (CI) = 1.2-2.1). Clinical conditions associated with relocation included stroke (OR: 2.0, 95% CI: 1.2-3.3), angina (OR: 1.6, 95% CI: 1.0-2.6), and congestive heart failure (OR: 1.5, 95% CI: 1.0-2.1).

CONCLUSIONS: Major incident cardiovascular disease may increase the probability of residential relocation in older adults. Case-crossover analyses represent an opportunity to investigate triggering events, but finer temporal resolution would be crucial for future research on residential relocations.

%B J Environ Public Health %V 2014 %P 951971 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24782900?dopt=Abstract %R 10.1155/2014/951971 %0 Journal Article %J Atherosclerosis %D 2014 %T Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study. %A Odden, Michelle C %A Shlipak, Michael G %A Whitson, Heather E %A Katz, Ronit %A Kearney, Patricia M %A deFilippi, Chris %A Shastri, Shani %A Sarnak, Mark J %A Siscovick, David S %A Cushman, Mary %A Psaty, Bruce M %A Newman, Anne B %K Aged %K Aged, 80 and over %K Blood Pressure %K C-Reactive Protein %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K Diabetes Complications %K Diabetes Mellitus %K Female %K Humans %K Inflammation %K Kidney %K Kidney Diseases %K Lipids %K Male %K Natriuretic Peptide, Brain %K Obesity %K Peptide Fragments %K Risk Factors %X

OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.

METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).

RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).

CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.

%B Atherosclerosis %V 237 %P 336-42 %8 2014 Nov %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25303772?dopt=Abstract %R 10.1016/j.atherosclerosis.2014.09.012 %0 Journal Article %J Am J Hum Genet %D 2014 %T Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. %A Lange, Leslie A %A Hu, Youna %A Zhang, He %A Xue, Chenyi %A Schmidt, Ellen M %A Tang, Zheng-Zheng %A Bizon, Chris %A Lange, Ethan M %A Smith, Joshua D %A Turner, Emily H %A Jun, Goo %A Kang, Hyun Min %A Peloso, Gina %A Auer, Paul %A Li, Kuo-Ping %A Flannick, Jason %A Zhang, Ji %A Fuchsberger, Christian %A Gaulton, Kyle %A Lindgren, Cecilia %A Locke, Adam %A Manning, Alisa %A Sim, Xueling %A Rivas, Manuel A %A Holmen, Oddgeir L %A Gottesman, Omri %A Lu, Yingchang %A Ruderfer, Douglas %A Stahl, Eli A %A Duan, Qing %A Li, Yun %A Durda, Peter %A Jiao, Shuo %A Isaacs, Aaron %A Hofman, Albert %A Bis, Joshua C %A Correa, Adolfo %A Griswold, Michael E %A Jakobsdottir, Johanna %A Smith, Albert V %A Schreiner, Pamela J %A Feitosa, Mary F %A Zhang, Qunyuan %A Huffman, Jennifer E %A Crosby, Jacy %A Wassel, Christina L %A Do, Ron %A Franceschini, Nora %A Martin, Lisa W %A Robinson, Jennifer G %A Assimes, Themistocles L %A Crosslin, David R %A Rosenthal, Elisabeth A %A Tsai, Michael %A Rieder, Mark J %A Farlow, Deborah N %A Folsom, Aaron R %A Lumley, Thomas %A Fox, Ervin R %A Carlson, Christopher S %A Peters, Ulrike %A Jackson, Rebecca D %A van Duijn, Cornelia M %A Uitterlinden, André G %A Levy, Daniel %A Rotter, Jerome I %A Taylor, Herman A %A Gudnason, Vilmundur %A Siscovick, David S %A Fornage, Myriam %A Borecki, Ingrid B %A Hayward, Caroline %A Rudan, Igor %A Chen, Y Eugene %A Bottinger, Erwin P %A Loos, Ruth J F %A Sætrom, Pål %A Hveem, Kristian %A Boehnke, Michael %A Groop, Leif %A McCarthy, Mark %A Meitinger, Thomas %A Ballantyne, Christie M %A Gabriel, Stacey B %A O'Donnell, Christopher J %A Post, Wendy S %A North, Kari E %A Reiner, Alexander P %A Boerwinkle, Eric %A Psaty, Bruce M %A Altshuler, David %A Kathiresan, Sekar %A Lin, Dan-Yu %A Jarvik, Gail P %A Cupples, L Adrienne %A Kooperberg, Charles %A Wilson, James G %A Nickerson, Deborah A %A Abecasis, Goncalo R %A Rich, Stephen S %A Tracy, Russell P %A Willer, Cristen J %K Adult %K Aged %K Apolipoproteins E %K Cholesterol, LDL %K Cohort Studies %K Dyslipidemias %K Exome %K Female %K Follow-Up Studies %K Gene Frequency %K Genetic Code %K Genome-Wide Association Study %K Genotype %K Humans %K Lipase %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Proprotein Convertase 9 %K Proprotein Convertases %K Receptors, LDL %K Sequence Analysis, DNA %K Serine Endopeptidases %X

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

%B Am J Hum Genet %V 94 %P 233-45 %8 2014 Feb 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract %R 10.1016/j.ajhg.2014.01.010 %0 Journal Article %J Metabolism %D 2015 %T Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study. %A Agarwal, Isha %A Glazer, Nicole L %A Barasch, Eddy %A Djoussé, Luc %A Gottdiener, John S %A Ix, Joachim H %A Kizer, Jorge R %A Rimm, Eric B %A Siscovick, David S %A King, George L %A Mukamal, Ken J %K Aged %K Aged, 80 and over %K Biomarkers %K Blood Glucose %K Cardiovascular System %K Cross-Sectional Studies %K Diabetes Complications %K Diabetes Mellitus %K Fatty Acids, Nonesterified %K Female %K Fibrosis %K Health %K Humans %K Insulin %K Insulin Resistance %K Male %K Metabolic Diseases %K Peptide Fragments %K Procollagen %K Transforming Growth Factor beta %X

AIM: Fibrosis is one postulated pathway by which diabetes produces cardiac and other systemic complications. Our aim was to determine which metabolic parameters are associated with circulating fibrosis-related biomarkers transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP).

METHODS: We used linear regression to determine the cross-sectional associations of diverse metabolic parameters, including fasting glucose, fasting insulin, body mass index, fatty acid binding protein 4, and non-esterified fatty acids, with circulating levels of TGF-β (n = 1559) and PIIINP (n = 3024) among community-living older adults in the Cardiovascular Health Study.

RESULTS: Among the main metabolic parameters we examined, only fasting glucose was associated with TGF-β (P = 0.03). In contrast, multiple metabolic parameters were associated with PIIINP, including fasting insulin, body mass index, and non-esterified fatty acids (P<0.001, P<0.001, P=0.001, respectively). These associations remained statistically significant after mutual adjustment, except the association between BMI and PIIINP.

CONCLUSIONS: Isolated hyperglycemia is associated with higher serum concentrations of TGF-β, while a broader phenotype of insulin resistance is associated with higher serum PIIINP. Whether simultaneous pharmacologic targeting of these two metabolic phenotypes can synergistically reduce the risk of cardiac and other manifestations of fibrosis remains to be determined.

%B Metabolism %V 64 %P 1316-23 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26282733?dopt=Abstract %R 10.1016/j.metabol.2015.07.013 %0 Journal Article %J Diabetes Care %D 2015 %T Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study. %A Wang, Qianyi %A Imamura, Fumiaki %A Ma, Wenjie %A Wang, Molin %A Lemaitre, Rozenn N %A King, Irena B %A Song, Xiaoling %A Biggs, Mary L %A Delaney, Joseph A %A Mukamal, Kenneth J %A Djoussé, Luc %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Biomarkers %K Diabetes Mellitus, Type 2 %K Diabetic Angiopathies %K Dietary Fats, Unsaturated %K Epidemiologic Methods %K Female %K Food Habits %K Humans %K Male %K Phospholipids %K Trans Fatty Acids %X

OBJECTIVE: To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment.

RESEARCH DESIGN AND METHODS: In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 ± 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards.

RESULTS: In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95% CI 1.04-2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20-3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03-1.86], P-trend = 0.02), t-18:1 (1.32 [1.00-1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05-1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained.

CONCLUSIONS: Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.

%B Diabetes Care %V 38 %P 1099-107 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25784660?dopt=Abstract %R 10.2337/dc14-2101 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians. %A Fretts, Amanda M %A Follis, Jack L %A Nettleton, Jennifer A %A Lemaitre, Rozenn N %A Ngwa, Julius S %A Wojczynski, Mary K %A Kalafati, Ioanna Panagiota %A Varga, Tibor V %A Frazier-Wood, Alexis C %A Houston, Denise K %A Lahti, Jari %A Ericson, Ulrika %A van den Hooven, Edith H %A Mikkilä, Vera %A Kiefte-de Jong, Jessica C %A Mozaffarian, Dariush %A Rice, Kenneth %A Renstrom, Frida %A North, Kari E %A McKeown, Nicola M %A Feitosa, Mary F %A Kanoni, Stavroula %A Smith, Caren E %A Garcia, Melissa E %A Tiainen, Anna-Maija %A Sonestedt, Emily %A Manichaikul, Ani %A van Rooij, Frank J A %A Dimitriou, Maria %A Raitakari, Olli %A Pankow, James S %A Djoussé, Luc %A Province, Michael A %A Hu, Frank B %A Lai, Chao-Qiang %A Keller, Margaux F %A Perälä, Mia-Maria %A Rotter, Jerome I %A Hofman, Albert %A Graff, Misa %A Kähönen, Mika %A Mukamal, Kenneth %A Johansson, Ingegerd %A Ordovas, Jose M %A Liu, Yongmei %A Männistö, Satu %A Uitterlinden, André G %A Deloukas, Panos %A Seppälä, Ilkka %A Psaty, Bruce M %A Cupples, L Adrienne %A Borecki, Ingrid B %A Franks, Paul W %A Arnett, Donna K %A Nalls, Mike A %A Eriksson, Johan G %A Orho-Melander, Marju %A Franco, Oscar H %A Lehtimäki, Terho %A Dedoussis, George V %A Meigs, James B %A Siscovick, David S %K Blood Glucose %K Cohort Studies %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hyperglycemia %K Hyperinsulinism %K Insulin %K Insulin Resistance %K Insulin-Secreting Cells %K Meat %K Meat Products %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

%B Am J Clin Nutr %V 102 %P 1266-78 %8 2015 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26354543?dopt=Abstract %R 10.3945/ajcn.114.101238 %0 Journal Article %J JACC Heart Fail %D 2015 %T Contribution of Major Lifestyle Risk Factors for Incident Heart Failure in Older Adults: The Cardiovascular Health Study. %A Del Gobbo, Liana C %A Kalantarian, Shadi %A Imamura, Fumiaki %A Lemaitre, Rozenn %A Siscovick, David S %A Psaty, Bruce M %A Mozaffarian, Dariush %K Aged %K Alcohol Drinking %K Cohort Studies %K Diet %K Female %K Heart Failure %K Humans %K Incidence %K Male %K Motor Activity %K Obesity %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Sedentary Lifestyle %K Smoking %K United States %X

OBJECTIVES: The goal of this study was to determine the relative contribution of major lifestyle factors on the development of heart failure (HF) in older adults.

BACKGROUND: HF incurs high morbidity, mortality, and health care costs among adults ≥65 years of age, which is the most rapidly growing segment of the U.S.

METHODS: We prospectively investigated separate and combined associations of lifestyle risk factors with incident HF (1,380 cases) over 21.5 years among 4,490 men and women in the Cardiovascular Health Study, which is a community-based cohort of older adults. Lifestyle factors included 4 dietary patterns (Alternative Healthy Eating Index, Dietary Approaches to Stop Hypertension, an American Heart Association 2020 dietary goals score, and a Biologic pattern, which was constructed using previous knowledge of cardiovascular disease dietary risk factors), 4 physical activity metrics (exercise intensity, walking pace, energy expended in leisure activity, and walking distance), alcohol intake, smoking, and obesity.

RESULTS: No dietary pattern was associated with developing HF (p > 0.05). Walking pace and leisure activity were associated with a 26% and 22% lower risk of HF, respectively (pace >3 mph vs. <2 mph; hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.63 to 0.86; leisure activity ≥845 kcal/week vs. <845 kcal/week; HR: 0.78; 95% CI: 0.69 to 0.87). Modest alcohol intake, maintaining a body mass index <30 kg/m(2), and not smoking were also independently associated with a lower risk of HF. Participants with ≥4 healthy lifestyle factors had a 45% (HR: 0.55; 95% CI: 0.42 to 0.74) lower risk of HF. Heterogeneity by age, sex, cardiovascular disease, hypertension medication use, and diabetes was not observed.

CONCLUSIONS: Among older U.S. adults, physical activity, modest alcohol intake, avoiding obesity, and not smoking, but not dietary patterns, were associated with a lower risk of HF.

%B JACC Heart Fail %V 3 %P 520-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/26160366?dopt=Abstract %R 10.1016/j.jchf.2015.02.009 %0 Journal Article %J Clin J Am Soc Nephrol %D 2015 %T Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD. %A Bansal, Nisha %A Katz, Ronit %A de Boer, Ian H %A Peralta, Carmen A %A Fried, Linda F %A Siscovick, David S %A Rifkin, Dena E %A Hirsch, Calvin %A Cummings, Steven R %A Harris, Tamara B %A Kritchevsky, Stephen B %A Sarnak, Mark J %A Shlipak, Michael G %A Ix, Joachim H %K Age Factors %K Aged %K Aged, 80 and over %K Albuminuria %K Continental Population Groups %K Creatinine %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Male %K Proportional Hazards Models %K Regression Analysis %K Renal Insufficiency, Chronic %K Risk Factors %K Sex Factors %K Smoking %K Stroke %X

BACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study.

RESULTS: The development cohort included 828 participants who had a mean age of 80 (±5.6) years and an eGFR of 47 (±11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 (±2.8) years and an eGFR of 50 (±9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8% among participants with the lowest scores to 83.6% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95% confidence interval, 0.64 to 0.74).

CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making.

%B Clin J Am Soc Nephrol %V 10 %P 363-71 %8 2015 Mar 6 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25710804?dopt=Abstract %R 10.2215/CJN.04650514 %0 Journal Article %J Mol Nutr Food Res %D 2015 %T Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium. %A Smith, Caren E %A Follis, Jack L %A Nettleton, Jennifer A %A Foy, Millennia %A Wu, Jason H Y %A Ma, Yiyi %A Tanaka, Toshiko %A Manichakul, Ani W %A Wu, Hongyu %A Chu, Audrey Y %A Steffen, Lyn M %A Fornage, Myriam %A Mozaffarian, Dariush %A Kabagambe, Edmond K %A Ferruci, Luigi %A Chen, Yii-Der Ida %A Rich, Stephen S %A Djoussé, Luc %A Ridker, Paul M %A Tang, Weihong %A McKnight, Barbara %A Tsai, Michael Y %A Bandinelli, Stefania %A Rotter, Jerome I %A Hu, Frank B %A Chasman, Daniel I %A Psaty, Bruce M %A Arnett, Donna K %A King, Irena B %A Sun, Qi %A Wang, Lu %A Lumley, Thomas %A Chiuve, Stephanie E %A Siscovick, David S %A Ordovas, Jose M %A Lemaitre, Rozenn N %K Acetyltransferases %K Acyltransferases %K Adaptor Proteins, Signal Transducing %K Carboxy-Lyases %K Diet %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Erythrocyte Membrane %K Fatty Acid Desaturases %K Fatty Acids %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

SCOPE: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.

METHODS AND RESULTS: We conducted meta-analyses (N = 11 668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.

CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.

%B Mol Nutr Food Res %V 59 %P 1373-83 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25626431?dopt=Abstract %R 10.1002/mnfr.201400734 %0 Journal Article %J Nature %D 2015 %T Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. %A Do, Ron %A Stitziel, Nathan O %A Won, Hong-Hee %A Jørgensen, Anders Berg %A Duga, Stefano %A Angelica Merlini, Pier %A Kiezun, Adam %A Farrall, Martin %A Goel, Anuj %A Zuk, Or %A Guella, Illaria %A Asselta, Rosanna %A Lange, Leslie A %A Peloso, Gina M %A Auer, Paul L %A Girelli, Domenico %A Martinelli, Nicola %A Farlow, Deborah N %A DePristo, Mark A %A Roberts, Robert %A Stewart, Alexander F R %A Saleheen, Danish %A Danesh, John %A Epstein, Stephen E %A Sivapalaratnam, Suthesh %A Hovingh, G Kees %A Kastelein, John J %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Shah, Svati H %A Kraus, William E %A Davies, Robert %A Nikpay, Majid %A Johansen, Christopher T %A Wang, Jian %A Hegele, Robert A %A Hechter, Eliana %A März, Winfried %A Kleber, Marcus E %A Huang, Jie %A Johnson, Andrew D %A Li, Mingyao %A Burke, Greg L %A Gross, Myron %A Liu, Yongmei %A Assimes, Themistocles L %A Heiss, Gerardo %A Lange, Ethan M %A Folsom, Aaron R %A Taylor, Herman A %A Olivieri, Oliviero %A Hamsten, Anders %A Clarke, Robert %A Reilly, Dermot F %A Yin, Wu %A Rivas, Manuel A %A Donnelly, Peter %A Rossouw, Jacques E %A Psaty, Bruce M %A Herrington, David M %A Wilson, James G %A Rich, Stephen S %A Bamshad, Michael J %A Tracy, Russell P %A Cupples, L Adrienne %A Rader, Daniel J %A Reilly, Muredach P %A Spertus, John A %A Cresci, Sharon %A Hartiala, Jaana %A Tang, W H Wilson %A Hazen, Stanley L %A Allayee, Hooman %A Reiner, Alex P %A Carlson, Christopher S %A Kooperberg, Charles %A Jackson, Rebecca D %A Boerwinkle, Eric %A Lander, Eric S %A Schwartz, Stephen M %A Siscovick, David S %A McPherson, Ruth %A Tybjaerg-Hansen, Anne %A Abecasis, Goncalo R %A Watkins, Hugh %A Nickerson, Deborah A %A Ardissino, Diego %A Sunyaev, Shamil R %A O'Donnell, Christopher J %A Altshuler, David %A Gabriel, Stacey %A Kathiresan, Sekar %K Age Factors %K Age of Onset %K Alleles %K Apolipoproteins A %K Case-Control Studies %K Cholesterol, LDL %K Coronary Artery Disease %K Exome %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation %K Myocardial Infarction %K National Heart, Lung, and Blood Institute (U.S.) %K Receptors, LDL %K Triglycerides %K United States %X

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

%B Nature %V 518 %P 102-6 %8 2015 Feb 5 %G eng %N 7537 %1 http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract %R 10.1038/nature13917 %0 Journal Article %J Atherosclerosis %D 2015 %T Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies. %A Laugsand, Lars E %A Ix, Joachim H %A Bartz, Traci M %A Djoussé, Luc %A Kizer, Jorge R %A Tracy, Russell P %A Dehghan, Abbas %A Rexrode, Kathryn %A Lopez, Oscar L %A Rimm, Eric B %A Siscovick, David S %A O'Donnell, Christopher J %A Newman, Anne %A Mukamal, Kenneth J %A Jensen, Majken K %K Aged %K Aged, 80 and over %K alpha-2-HS-Glycoprotein %K Carotid Intima-Media Thickness %K Coronary Vessels %K Female %K Genetic Variation %K Genotype %K Heart Diseases %K Humans %K Insulin Resistance %K Longitudinal Studies %K Male %K Mendelian Randomization Analysis %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Factors %K Vascular Calcification %X

BACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).

METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.

RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).

CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.

%B Atherosclerosis %V 243 %P 44-52 %8 2015 Nov %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26343871?dopt=Abstract %R 10.1016/j.atherosclerosis.2015.08.031 %0 Journal Article %J Atherosclerosis %D 2015 %T Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study. %A Agarwal, Isha %A Arnold, Alice %A Glazer, Nicole L %A Barasch, Eddy %A Djoussé, Luc %A Fitzpatrick, Annette L %A Gottdiener, John S %A Ix, Joachim H %A Jensen, Richard A %A Kizer, Jorge R %A Rimm, Eric B %A Siscovick, David S %A Tracy, Russell P %A Wong, Tien Y %A Mukamal, Kenneth J %K Aged %K Ankle Brachial Index %K Biomarkers %K Brachial Artery %K Carotid Artery Diseases %K Carotid Intima-Media Thickness %K Cross-Sectional Studies %K Female %K Fibrosis %K Humans %K Incidence %K Male %K Peptide Fragments %K Peripheral Arterial Disease %K Predictive Value of Tests %K Procollagen %K Prognosis %K Prospective Studies %K Retinal Diseases %K Risk Factors %K Transforming Growth Factor beta %K United States %K Vasodilation %X

OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.

METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.

RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR] = 1.36 per doubling of TGF-β, 95% confidence interval [CI] = 1.04, 1.78) and retinal venular diameter (1.63 μm per doubling of TGF-β, CI = 0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102 mm per doubling of PIIINP, CI = 0.029, 0.174) and impaired brachial artery reactivity (-0.20% change per doubling of PIIINP, CI = -0.39, -0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.

CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.

%B Atherosclerosis %V 239 %P 539-46 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25725316?dopt=Abstract %R 10.1016/j.atherosclerosis.2015.02.020 %0 Journal Article %J Hum Mol Genet %D 2015 %T Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. %A Nettleton, Jennifer A %A Follis, Jack L %A Ngwa, Julius S %A Smith, Caren E %A Ahmad, Shafqat %A Tanaka, Toshiko %A Wojczynski, Mary K %A Voortman, Trudy %A Lemaitre, Rozenn N %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Houston, Denise K %A Perälä, Mia-Maria %A Qi, Qibin %A Sonestedt, Emily %A Manichaikul, Ani %A Kanoni, Stavroula %A Ganna, Andrea %A Mikkilä, Vera %A North, Kari E %A Siscovick, David S %A Harald, Kennet %A McKeown, Nicola M %A Johansson, Ingegerd %A Rissanen, Harri %A Liu, Yongmei %A Lahti, Jari %A Hu, Frank B %A Bandinelli, Stefania %A Rukh, Gull %A Rich, Stephen %A Booij, Lisanne %A Dmitriou, Maria %A Ax, Erika %A Raitakari, Olli %A Mukamal, Kenneth %A Männistö, Satu %A Hallmans, Göran %A Jula, Antti %A Ericson, Ulrika %A Jacobs, David R %A van Rooij, Frank J A %A Deloukas, Panos %A Sjogren, Per %A Kähönen, Mika %A Djoussé, Luc %A Perola, Markus %A Barroso, Inês %A Hofman, Albert %A Stirrups, Kathleen %A Viikari, Jorma %A Uitterlinden, André G %A Kalafati, Ioanna P %A Franco, Oscar H %A Mozaffarian, Dariush %A Salomaa, Veikko %A Borecki, Ingrid B %A Knekt, Paul %A Kritchevsky, Stephen B %A Eriksson, Johan G %A Dedoussis, George V %A Qi, Lu %A Ferrucci, Luigi %A Orho-Melander, Marju %A Zillikens, M Carola %A Ingelsson, Erik %A Lehtimäki, Terho %A Renstrom, Frida %A Cupples, L Adrienne %A Loos, Ruth J F %A Franks, Paul W %K Adult %K Body Mass Index %K Case-Control Studies %K Diet, Western %K Epistasis, Genetic %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Obesity %K Polymorphism, Single Nucleotide %X

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.

%B Hum Mol Genet %V 24 %P 4728-38 %8 2015 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/25994509?dopt=Abstract %R 10.1093/hmg/ddv186 %0 Journal Article %J J Lipid Res %D 2015 %T Genetic loci associated with circulating levels of very long-chain saturated fatty acids. %A Lemaitre, Rozenn N %A King, Irena B %A Kabagambe, Edmond K %A Wu, Jason H Y %A McKnight, Barbara %A Manichaikul, Ani %A Guan, Weihua %A Sun, Qi %A Chasman, Daniel I %A Foy, Millennia %A Wang, Lu %A Zhu, Jingwen %A Siscovick, David S %A Tsai, Michael Y %A Arnett, Donna K %A Psaty, Bruce M %A Djoussé, Luc %A Chen, Yii-der I %A Tang, Weihong %A Weng, Lu-Chen %A Wu, Hongyu %A Jensen, Majken K %A Chu, Audrey Y %A Jacobs, David R %A Rich, Stephen S %A Mozaffarian, Dariush %A Steffen, Lyn %A Rimm, Eric B %A Hu, Frank B %A Ridker, Paul M %A Fornage, Myriam %A Friedlander, Yechiel %K Cohort Studies %K Fatty Acids %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %X

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

%B J Lipid Res %V 56 %P 176-84 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25378659?dopt=Abstract %R 10.1194/jlr.M052456 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. %A Mozaffarian, Dariush %A Kabagambe, Edmond K %A Johnson, Catherine O %A Lemaitre, Rozenn N %A Manichaikul, Ani %A Sun, Qi %A Foy, Millennia %A Wang, Lu %A Wiener, Howard %A Irvin, Marguerite R %A Rich, Stephen S %A Wu, Hongyu %A Jensen, Majken K %A Chasman, Daniel I %A Chu, Audrey Y %A Fornage, Myriam %A Steffen, Lyn %A King, Irena B %A McKnight, Barbara %A Psaty, Bruce M %A Djoussé, Luc %A Chen, Ida Y-D %A Wu, Jason H Y %A Siscovick, David S %A Ridker, Paul M %A Tsai, Michael Y %A Rimm, Eric B %A Hu, Frank B %A Arnett, Donna K %K African Americans %K Arachidonic Acid %K Asian Americans %K Biomarkers %K European Continental Ancestry Group %K Fatty Acids, Omega-6 %K Gene Frequency %K Genetic Association Studies %K Genetic Loci %K Genotyping Techniques %K Humans %K Phospholipids %K Polymorphism, Single Nucleotide %K Trans Fatty Acids %X

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.

%B Am J Clin Nutr %V 101 %P 398-406 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25646338?dopt=Abstract %R 10.3945/ajcn.114.094557 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. %A Dashti, Hassan S %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Cade, Brian E %A Gottlieb, Daniel J %A Hruby, Adela %A Jacques, Paul F %A Lamon-Fava, Stefania %A Richardson, Kris %A Saxena, Richa %A Scheer, Frank A J L %A Kovanen, Leena %A Bartz, Traci M %A Perälä, Mia-Maria %A Jonsson, Anna %A Frazier-Wood, Alexis C %A Kalafati, Ioanna-Panagiota %A Mikkilä, Vera %A Partonen, Timo %A Lemaitre, Rozenn N %A Lahti, Jari %A Hernandez, Dena G %A Toft, Ulla %A Johnson, W Craig %A Kanoni, Stavroula %A Raitakari, Olli T %A Perola, Markus %A Psaty, Bruce M %A Ferrucci, Luigi %A Grarup, Niels %A Highland, Heather M %A Rallidis, Loukianos %A Kähönen, Mika %A Havulinna, Aki S %A Siscovick, David S %A Räikkönen, Katri %A Jørgensen, Torben %A Rotter, Jerome I %A Deloukas, Panos %A Viikari, Jorma S A %A Mozaffarian, Dariush %A Linneberg, Allan %A Seppälä, Ilkka %A Hansen, Torben %A Salomaa, Veikko %A Gharib, Sina A %A Eriksson, Johan G %A Bandinelli, Stefania %A Pedersen, Oluf %A Rich, Stephen S %A Dedoussis, George %A Lehtimäki, Terho %A Ordovas, Jose M %K Adult %K Body Mass Index %K CLOCK Proteins %K Cohort Studies %K Cross-Sectional Studies %K Diet %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Fatty Acids, Unsaturated %K Female %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Sleep %K Young Adult %X

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.

%B Am J Clin Nutr %V 101 %P 135-43 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25527757?dopt=Abstract %R 10.3945/ajcn.114.095026 %0 Journal Article %J Heart %D 2015 %T Higher circulating adiponectin levels are associated with increased risk of atrial fibrillation in older adults. %A Macheret, Fima %A Bartz, Traci M %A Djoussé, Luc %A Ix, Joachim H %A Mukamal, Kenneth J %A Zieman, Susan J %A Siscovick, David S %A Tracy, Russell P %A Heckbert, Susan R %A Psaty, Bruce M %A Kizer, Jorge R %K Adiponectin %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Atrial Fibrillation %K Biomarkers %K Female %K Humans %K Incidence %K Linear Models %K Male %K Multivariate Analysis %K Natriuretic Peptide, Brain %K Peptide Fragments %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %K Up-Regulation %X

BACKGROUND: Adiponectin has cardioprotective properties, suggesting that lower levels seen in obesity and diabetes could heighten risk of atrial fibrillation (AF). Among older adults, however, higher adiponectin has been linked to greater incidence of adverse outcomes associated with AF, although recent reports have shown this association to be U-shaped. We postulated that higher adiponectin would be linked to increased risk for AF in older adults in a U-shaped manner.

METHODS: We examined the associations of total and high-molecular-weight (HMW) adiponectin with incident AF among individuals free of prevalent cardiovascular disease (CVD) participating in a population-based cohort study of older adults (n=3190; age=74±5 years).

RESULTS: During median follow-up of 11.4 years, there were 886 incident AF events. Adjusted cubic splines showed a positive and linear association between adiponectin and incident AF. After adjusting for potential confounders, including amino-terminal pro-B-type natriuretic peptide 1-76, the HR (95% CI) for AF per SD increase in total adiponectin was 1.14 (1.05 to 1.24), while that for HMW adiponectin was 1.17 (1.08 to 1.27). Additional adjustment for putative mediators, including subclinical CVD, diabetes, lipids and inflammation, did not significantly affect these estimates.

CONCLUSIONS: The present findings demonstrate that higher, not lower, levels of adiponectin are independently associated with increased risk of AF in older adults despite its documented cardiometabolic benefits. Additional work is necessary to determine if adiponectin is a marker of failed counter-regulatory pathways or whether this hormone is directly harmful in the setting of or as a result of advanced age.

%B Heart %V 101 %P 1368-74 %8 2015 Sep %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/25855796?dopt=Abstract %R 10.1136/heartjnl-2014-307015 %0 Journal Article %J Lancet %D 2015 %T HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. %A Swerdlow, Daniel I %A Preiss, David %A Kuchenbaecker, Karoline B %A Holmes, Michael V %A Engmann, Jorgen E L %A Shah, Tina %A Sofat, Reecha %A Stender, Stefan %A Johnson, Paul C D %A Scott, Robert A %A Leusink, Maarten %A Verweij, Niek %A Sharp, Stephen J %A Guo, Yiran %A Giambartolomei, Claudia %A Chung, Christina %A Peasey, Anne %A Amuzu, Antoinette %A Li, KaWah %A Palmen, Jutta %A Howard, Philip %A Cooper, Jackie A %A Drenos, Fotios %A Li, Yun R %A Lowe, Gordon %A Gallacher, John %A Stewart, Marlene C W %A Tzoulaki, Ioanna %A Buxbaum, Sarah G %A van der A, Daphne L %A Forouhi, Nita G %A Onland-Moret, N Charlotte %A van der Schouw, Yvonne T %A Schnabel, Renate B %A Hubacek, Jaroslav A %A Kubinova, Ruzena %A Baceviciene, Migle %A Tamosiunas, Abdonas %A Pajak, Andrzej %A Topor-Madry, Roman %A Stepaniak, Urszula %A Malyutina, Sofia %A Baldassarre, Damiano %A Sennblad, Bengt %A Tremoli, Elena %A de Faire, Ulf %A Veglia, Fabrizio %A Ford, Ian %A Jukema, J Wouter %A Westendorp, Rudi G J %A de Borst, Gert Jan %A de Jong, Pim A %A Algra, Ale %A Spiering, Wilko %A Maitland-van der Zee, Anke H %A Klungel, Olaf H %A de Boer, Anthonius %A Doevendans, Pieter A %A Eaton, Charles B %A Robinson, Jennifer G %A Duggan, David %A Kjekshus, John %A Downs, John R %A Gotto, Antonio M %A Keech, Anthony C %A Marchioli, Roberto %A Tognoni, Gianni %A Sever, Peter S %A Poulter, Neil R %A Waters, David D %A Pedersen, Terje R %A Amarenco, Pierre %A Nakamura, Haruo %A McMurray, John J V %A Lewsey, James D %A Chasman, Daniel I %A Ridker, Paul M %A Maggioni, Aldo P %A Tavazzi, Luigi %A Ray, Kausik K %A Seshasai, Sreenivasa Rao Kondapally %A Manson, JoAnn E %A Price, Jackie F %A Whincup, Peter H %A Morris, Richard W %A Lawlor, Debbie A %A Smith, George Davey %A Ben-Shlomo, Yoav %A Schreiner, Pamela J %A Fornage, Myriam %A Siscovick, David S %A Cushman, Mary %A Kumari, Meena %A Wareham, Nick J %A Verschuren, W M Monique %A Redline, Susan %A Patel, Sanjay R %A Whittaker, John C %A Hamsten, Anders %A Delaney, Joseph A %A Dale, Caroline %A Gaunt, Tom R %A Wong, Andrew %A Kuh, Diana %A Hardy, Rebecca %A Kathiresan, Sekar %A Castillo, Berta A %A van der Harst, Pim %A Brunner, Eric J %A Tybjaerg-Hansen, Anne %A Marmot, Michael G %A Krauss, Ronald M %A Tsai, Michael %A Coresh, Josef %A Hoogeveen, Ronald C %A Psaty, Bruce M %A Lange, Leslie A %A Hakonarson, Hakon %A Dudbridge, Frank %A Humphries, Steve E %A Talmud, Philippa J %A Kivimaki, Mika %A Timpson, Nicholas J %A Langenberg, Claudia %A Asselbergs, Folkert W %A Voevoda, Mikhail %A Bobak, Martin %A Pikhart, Hynek %A Wilson, James G %A Reiner, Alex P %A Keating, Brendan J %A Hingorani, Aroon D %A Sattar, Naveed %K Aged %K Body Mass Index %K Body Weight %K Cholesterol, HDL %K Cholesterol, LDL %K Diabetes Mellitus, Type 2 %K Female %K Genetic Testing %K Humans %K Hydroxymethylglutaryl CoA Reductases %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Randomized Controlled Trials as Topic %K Risk Factors %X

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).

INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

FUNDING: The funding sources are cited at the end of the paper.

%B Lancet %V 385 %P 351-61 %8 2015 Jan 24 %G eng %N 9965 %1 http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract %R 10.1016/S0140-6736(14)61183-1 %0 Journal Article %J Nat Commun %D 2015 %T Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. %A Wessel, Jennifer %A Chu, Audrey Y %A Willems, Sara M %A Wang, Shuai %A Yaghootkar, Hanieh %A Brody, Jennifer A %A Dauriz, Marco %A Hivert, Marie-France %A Raghavan, Sridharan %A Lipovich, Leonard %A Hidalgo, Bertha %A Fox, Keolu %A Huffman, Jennifer E %A An, Ping %A Lu, Yingchang %A Rasmussen-Torvik, Laura J %A Grarup, Niels %A Ehm, Margaret G %A Li, Li %A Baldridge, Abigail S %A Stančáková, Alena %A Abrol, Ravinder %A Besse, Céline %A Boland, Anne %A Bork-Jensen, Jette %A Fornage, Myriam %A Freitag, Daniel F %A Garcia, Melissa E %A Guo, Xiuqing %A Hara, Kazuo %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Lange, Leslie A %A Layton, Jill C %A Li, Man %A Hua Zhao, Jing %A Meidtner, Karina %A Morrison, Alanna C %A Nalls, Mike A %A Peters, Marjolein J %A Sabater-Lleal, Maria %A Schurmann, Claudia %A Silveira, Angela %A Smith, Albert V %A Southam, Lorraine %A Stoiber, Marcus H %A Strawbridge, Rona J %A Taylor, Kent D %A Varga, Tibor V %A Allin, Kristine H %A Amin, Najaf %A Aponte, Jennifer L %A Aung, Tin %A Barbieri, Caterina %A Bihlmeyer, Nathan A %A Boehnke, Michael %A Bombieri, Cristina %A Bowden, Donald W %A Burns, Sean M %A Chen, Yuning %A Chen, Yii-DerI %A Cheng, Ching-Yu %A Correa, Adolfo %A Czajkowski, Jacek %A Dehghan, Abbas %A Ehret, Georg B %A Eiriksdottir, Gudny %A Escher, Stefan A %A Farmaki, Aliki-Eleni %A Frånberg, Mattias %A Gambaro, Giovanni %A Giulianini, Franco %A Goddard, William A %A Goel, Anuj %A Gottesman, Omri %A Grove, Megan L %A Gustafsson, Stefan %A Hai, Yang %A Hallmans, Göran %A Heo, Jiyoung %A Hoffmann, Per %A Ikram, Mohammad K %A Jensen, Richard A %A Jørgensen, Marit E %A Jørgensen, Torben %A Karaleftheri, Maria %A Khor, Chiea C %A Kirkpatrick, Andrea %A Kraja, Aldi T %A Kuusisto, Johanna %A Lange, Ethan M %A Lee, I T %A Lee, Wen-Jane %A Leong, Aaron %A Liao, Jiemin %A Liu, Chunyu %A Liu, Yongmei %A Lindgren, Cecilia M %A Linneberg, Allan %A Malerba, Giovanni %A Mamakou, Vasiliki %A Marouli, Eirini %A Maruthur, Nisa M %A Matchan, Angela %A McKean-Cowdin, Roberta %A McLeod, Olga %A Metcalf, Ginger A %A Mohlke, Karen L %A Muzny, Donna M %A Ntalla, Ioanna %A Palmer, Nicholette D %A Pasko, Dorota %A Peter, Andreas %A Rayner, Nigel W %A Renstrom, Frida %A Rice, Ken %A Sala, Cinzia F %A Sennblad, Bengt %A Serafetinidis, Ioannis %A Smith, Jennifer A %A Soranzo, Nicole %A Speliotes, Elizabeth K %A Stahl, Eli A %A Stirrups, Kathleen %A Tentolouris, Nikos %A Thanopoulou, Anastasia %A Torres, Mina %A Traglia, Michela %A Tsafantakis, Emmanouil %A Javad, Sundas %A Yanek, Lisa R %A Zengini, Eleni %A Becker, Diane M %A Bis, Joshua C %A Brown, James B %A Cupples, L Adrienne %A Hansen, Torben %A Ingelsson, Erik %A Karter, Andrew J %A Lorenzo, Carlos %A Mathias, Rasika A %A Norris, Jill M %A Peloso, Gina M %A Sheu, Wayne H-H %A Toniolo, Daniela %A Vaidya, Dhananjay %A Varma, Rohit %A Wagenknecht, Lynne E %A Boeing, Heiner %A Bottinger, Erwin P %A Dedoussis, George %A Deloukas, Panos %A Ferrannini, Ele %A Franco, Oscar H %A Franks, Paul W %A Gibbs, Richard A %A Gudnason, Vilmundur %A Hamsten, Anders %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A Hofman, Albert %A Jansson, Jan-Håkan %A Langenberg, Claudia %A Launer, Lenore J %A Levy, Daniel %A Oostra, Ben A %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Padmanabhan, Sandosh %A Pankow, James S %A Polasek, Ozren %A Province, Michael A %A Rich, Stephen S %A Ridker, Paul M %A Rudan, Igor %A Schulze, Matthias B %A Smith, Blair H %A Uitterlinden, André G %A Walker, Mark %A Watkins, Hugh %A Wong, Tien Y %A Zeggini, Eleftheria %A Laakso, Markku %A Borecki, Ingrid B %A Chasman, Daniel I %A Pedersen, Oluf %A Psaty, Bruce M %A Tai, E Shyong %A van Duijn, Cornelia M %A Wareham, Nicholas J %A Waterworth, Dawn M %A Boerwinkle, Eric %A Kao, W H Linda %A Florez, Jose C %A Loos, Ruth J F %A Wilson, James G %A Frayling, Timothy M %A Siscovick, David S %A Dupuis, Josée %A Rotter, Jerome I %A Meigs, James B %A Scott, Robert A %A Goodarzi, Mark O %K African Continental Ancestry Group %K Blood Glucose %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Exome %K Fasting %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Glucagon-Like Peptide-1 Receptor %K Glucose-6-Phosphatase %K Humans %K Insulin %K Mutation Rate %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %X

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.

%B Nat Commun %V 6 %P 5897 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract %R 10.1038/ncomms6897 %0 Journal Article %J Eur Heart J %D 2015 %T Mendelian randomization of blood lipids for coronary heart disease. %A Holmes, Michael V %A Asselbergs, Folkert W %A Palmer, Tom M %A Drenos, Fotios %A Lanktree, Matthew B %A Nelson, Christopher P %A Dale, Caroline E %A Padmanabhan, Sandosh %A Finan, Chris %A Swerdlow, Daniel I %A Tragante, Vinicius %A van Iperen, Erik P A %A Sivapalaratnam, Suthesh %A Shah, Sonia %A Elbers, Clara C %A Shah, Tina %A Engmann, Jorgen %A Giambartolomei, Claudia %A White, Jon %A Zabaneh, Delilah %A Sofat, Reecha %A McLachlan, Stela %A Doevendans, Pieter A %A Balmforth, Anthony J %A Hall, Alistair S %A North, Kari E %A Almoguera, Berta %A Hoogeveen, Ron C %A Cushman, Mary %A Fornage, Myriam %A Patel, Sanjay R %A Redline, Susan %A Siscovick, David S %A Tsai, Michael Y %A Karczewski, Konrad J %A Hofker, Marten H %A Verschuren, W Monique %A Bots, Michiel L %A van der Schouw, Yvonne T %A Melander, Olle %A Dominiczak, Anna F %A Morris, Richard %A Ben-Shlomo, Yoav %A Price, Jackie %A Kumari, Meena %A Baumert, Jens %A Peters, Annette %A Thorand, Barbara %A Koenig, Wolfgang %A Gaunt, Tom R %A Humphries, Steve E %A Clarke, Robert %A Watkins, Hugh %A Farrall, Martin %A Wilson, James G %A Rich, Stephen S %A de Bakker, Paul I W %A Lange, Leslie A %A Davey Smith, George %A Reiner, Alex P %A Talmud, Philippa J %A Kivimaki, Mika %A Lawlor, Debbie A %A Dudbridge, Frank %A Samani, Nilesh J %A Keating, Brendan J %A Hingorani, Aroon D %A Casas, Juan P %K Case-Control Studies %K Cholesterol, HDL %K Coronary Artery Disease %K Female %K Gene Frequency %K Genotype %K Genotyping Techniques %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Assessment %K Triglycerides %X

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

%B Eur Heart J %V 36 %P 539-50 %8 2015 Mar 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24474739?dopt=Abstract %R 10.1093/eurheartj/eht571 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study. %A Lemaitre, Rozenn N %A Fretts, Amanda M %A Sitlani, Colleen M %A Biggs, Mary L %A Mukamal, Kenneth %A King, Irena B %A Song, Xiaoling %A Djoussé, Luc %A Siscovick, David S %A McKnight, Barbara %A Sotoodehnia, Nona %A Kizer, Jorge R %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Biomarkers %K Cross-Sectional Studies %K Diabetes Mellitus %K Diet %K Eicosanoic Acids %K Fatty Acids %K Fatty Acids, Nonesterified %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Observational Studies as Topic %K Palmitic Acid %K Phospholipids %K Prospective Studies %K Risk Factors %K Triglycerides %X

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47% lower risk of diabetes (95% CI: 23%, 63%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33% (95% CI: 6%, 53%; P-trend: 0.02) and 37% (95% CI: 11%, 55%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

%B Am J Clin Nutr %V 101 %P 1047-54 %8 2015 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25787996?dopt=Abstract %R 10.3945/ajcn.114.101857 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T Potassium and glucose measures in older adults: the Cardiovascular Health Study. %A Chatterjee, Ranee %A Biggs, Mary L %A de Boer, Ian H %A Brancati, Frederick L %A Svetkey, Laura P %A Barzilay, Joshua %A Djoussé, Luc %A Ix, Joachim H %A Kizer, Jorge R %A Siscovick, David S %A Mozaffarian, Dariush %A Edelman, David %A Mukamal, Kenneth J %K Aged %K Blood Glucose %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Humans %K Insulin %K Insulin Resistance %K Longitudinal Studies %K Male %K Multivariate Analysis %K Potassium %K Potassium, Dietary %K Risk Factors %K United States %X

BACKGROUND: We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.

METHODS: Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.

RESULTS: Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of -0.18 (-0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of -0.61 (-0.94, -0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.

CONCLUSIONS: Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 255-61 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24895271?dopt=Abstract %R 10.1093/gerona/glu071 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. %A Ma, Wenjie %A Wu, Jason H Y %A Wang, Qianyi %A Lemaitre, Rozenn N %A Mukamal, Kenneth J %A Djoussé, Luc %A King, Irena B %A Song, Xiaoling %A Biggs, Mary L %A Delaney, Joseph A %A Kizer, Jorge R %A Siscovick, David S %A Mozaffarian, Dariush %K Aged %K Biomarkers %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Follow-Up Studies %K Humans %K Incidence %K Lipogenesis %K Liver %K Male %K Palmitic Acid %K Phospholipids %K Prevalence %K Proportional Hazards Models %K Risk Factors %K Stearic Acids %K United States %K Up-Regulation %X

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

%B Am J Clin Nutr %V 101 %P 153-63 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25527759?dopt=Abstract %R 10.3945/ajcn.114.092601 %0 Journal Article %J Diabetes Care %D 2015 %T Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study. %A Strand, Linn Beate %A Carnethon, Mercedes %A Biggs, Mary Lou %A Djoussé, Luc %A Kaplan, Robert C %A Siscovick, David S %A Robbins, John A %A Redline, Susan %A Patel, Sanjay R %A Janszky, Imre %A Mukamal, Kenneth J %K Adult %K Aged %K Blood Glucose %K Cardiovascular System %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Glucose Tolerance Test %K Humans %K Incidence %K Insulin %K Insulin Resistance %K Male %K Middle Aged %K Sleep Apnea Syndromes %K Sleep Initiation and Maintenance Disorders %K Snoring %K United States %X

OBJECTIVE: We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults.

RESEARCH DESIGN AND METHODS: Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants ≥65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989-1994. In 1989-1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989-1990 and again in 1992-1993, 1994-1995, 1996-1997, and 1998-1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history.

RESULTS: Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19-2.86]), snoring (HR 1.27 [95% CI 0.95-1.71]), and daytime sleepiness (HR 1.54 [95% CI 1.13-2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes.

CONCLUSIONS: Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.

%B Diabetes Care %V 38 %P 2050-8 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26384390?dopt=Abstract %R 10.2337/dc15-0137 %0 Journal Article %J Kidney Int %D 2015 %T Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. %A Garimella, Pranav S %A Biggs, Mary L %A Katz, Ronit %A Ix, Joachim H %A Bennett, Michael R %A Devarajan, Prasad %A Kestenbaum, Bryan R %A Siscovick, David S %A Jensen, Majken K %A Shlipak, Michael G %A Chaves, Paulo H M %A Sarnak, Mark J %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Cardiovascular Diseases %K Case-Control Studies %K Creatinine %K Disease Progression %K Female %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Incidence %K Kidney Failure, Chronic %K Male %K Proportional Hazards Models %K Uromodulin %X

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

%B Kidney Int %V 88 %P 1126-34 %8 2015 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26154925?dopt=Abstract %R 10.1038/ki.2015.192 %0 Journal Article %J Heart %D 2015 %T Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults. %A Floyd, James S %A Sitlani, Colleen M %A Wiggins, Kerri L %A Wallace, Erin %A Suchy-Dicey, Astrid %A Abbasi, Siddique A %A Carnethon, Mercedes R %A Siscovick, David S %A Sotoodehnia, Nona %A Heckbert, Susan R %A McKnight, Barbara %A Rice, Kenneth M %A Psaty, Bruce M %K Aged %K Aged, 80 and over %K Cause of Death %K Electrocardiography %K Female %K Follow-Up Studies %K Heart Rate %K Humans %K Incidence %K Linear Models %K Male %K Myocardial Infarction %K Outcome Assessment (Health Care) %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Rest %K Risk Factors %K Time %K Washington %X

OBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.

METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.

RESULTS: 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.

CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.

%B Heart %V 101 %P 132-8 %8 2015 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25214500?dopt=Abstract %R 10.1136/heartjnl-2014-306046 %0 Journal Article %J J Am Coll Cardiol %D 2015 %T Ventricular Ectopy as a Predictor of Heart Failure and Death. %A Dukes, Jonathan W %A Dewland, Thomas A %A Vittinghoff, Eric %A Mandyam, Mala C %A Heckbert, Susan R %A Siscovick, David S %A Stein, Phyllis K %A Psaty, Bruce M %A Sotoodehnia, Nona %A Gottdiener, John S %A Marcus, Gregory M %K Aged %K Catheter Ablation %K Echocardiography %K Electrocardiography, Ambulatory %K Female %K Forecasting %K Heart Failure %K Humans %K Male %K Risk Factors %K Stroke Volume %K Ventricular Premature Complexes %X

BACKGROUND: Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown.

OBJECTIVES: The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort.

METHODS: We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.

RESULTS: Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio [OR]: 3.10; 95% confidence interval [CI]: 1.42 to 6.77; p = 0.005), a 48% increased risk of incident CHF (HR: 1.48; 95% CI: 1.08 to 2.04; p = 0.02), and a 31% increased risk of death (HR: 1.31; 95% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90% when PVCs included at least 0.7% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1% (95% CI: 1.2% to 14.9%).

CONCLUSIONS: In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.

%B J Am Coll Cardiol %V 66 %P 101-9 %8 2015 Jul 14 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26160626?dopt=Abstract %R 10.1016/j.jacc.2015.04.062 %0 Journal Article %J Heart %D 2016 %T Association of inflammatory, lipid and mineral markers with cardiac calcification in older adults. %A Bortnick, Anna E %A Bartz, Traci M %A Ix, Joachim H %A Chonchol, Michel %A Reiner, Alexander %A Cushman, Mary %A Owens, David %A Barasch, Eddy %A Siscovick, David S %A Gottdiener, John S %A Kizer, Jorge R %X

OBJECTIVE: Calcification of the aortic valve and adjacent structures involves inflammatory, lipid and mineral metabolism pathways. We hypothesised that circulating biomarkers reflecting these pathways are associated with cardiac calcification in older adults.

METHODS: We investigated the associations of various biomarkers with valvular and annular calcification in the Cardiovascular Health Study. Of the 5888 participants, up to 3585 were eligible after exclusions for missing biomarker, covariate or echocardiographic data. We evaluated analytes reflecting lipid (lipoprotein (Lp) (a), Lp-associated phospholipase A2 (LpPLA2) mass and activity), inflammatory (interleukin-6, soluble (s) CD14) and mineral metabolism (fetuin-A, fibroblast growth factor (FGF)-23) pathways that were measured within 5 years of echocardiography. The relationships of plasma biomarkers with aortic valve calcification (AVC), aortic annular calcification (AAC) and mitral annular calcification (MAC) were assessed with relative risk (RR) regression.

RESULTS: Calcification was prevalent: AVC 59%, AAC 45% and MAC 41%. After adjustment, Lp(a), LpPLA2 mass and activity and sCD14 were positively associated with AVC. RRs for AVC per SD (95% CI) were as follows: Lp(a), 1.051 (1.022 to 1.081); LpPLA2 mass, 1.036 (1.006 to 1.066) and LpPLA2 activity, 1.037 (1.004 to 1.071); sCD14, 1.039 (1.005 to 1.073). FGF-23 was positively associated with MAC, 1.040 (1.004 to 1.078) and fetuin-A was negatively associated, 0.949 (0.911 to 0.989). No biomarkers were significantly associated with AAC.

CONCLUSION: This study shows novel associations of circulating FGF-23 and fetuin-A with MAC, and LpPLA2 and sCD14 with AVC, confirming that previously reported for Lp(a). Further investigation of Lp and inflammatory pathways may provide added insight into the aetiology of AVC, while study of phosphate regulation may illuminate the pathogenesis of MAC.

%B Heart %8 2016 Jul 13 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/27411840?dopt=Abstract %R 10.1136/heartjnl-2016-309404 %0 Journal Article %J Eur J Hum Genet %D 2016 %T Association of the IGF1 gene with fasting insulin levels. %A Willems, Sara M %A Cornes, Belinda K %A Brody, Jennifer A %A Morrison, Alanna C %A Lipovich, Leonard %A Dauriz, Marco %A Chen, Yuning %A Liu, Ching-Ti %A Rybin, Denis V %A Gibbs, Richard A %A Muzny, Donna %A Pankow, James S %A Psaty, Bruce M %A Boerwinkle, Eric %A Rotter, Jerome I %A Siscovick, David S %A Vasan, Ramachandran S %A Kaplan, Robert C %A Isaacs, Aaron %A Dupuis, Josée %A van Duijn, Cornelia M %A Meigs, James B %X

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.

%B Eur J Hum Genet %V 24 %P 1337-43 %8 2016 Aug %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/26860063?dopt=Abstract %R 10.1038/ejhg.2016.4 %0 Journal Article %J J Nutr %D 2016 %T Associations of Plasma Phospholipid SFAs with Total and Cause-Specific Mortality in Older Adults Differ According to SFA Chain Length. %A Fretts, Amanda M %A Mozaffarian, Dariush %A Siscovick, David S %A King, Irena B %A McKnight, Barbara %A Psaty, Bruce M %A Rimm, Eric B %A Sitlani, Colleen %A Sacks, Frank M %A Song, Xiaoling %A Sotoodehnia, Nona %A Spiegelman, Donna %A Lemaitre, Rozenn N %K Aged %K Aged, 80 and over %K Cause of Death %K Diet %K Dietary Fats %K Eicosanoic Acids %K Fatty Acids %K Female %K Humans %K Male %K Mortality %K Palmitic Acid %K Phospholipids %K Prospective Studies %K Risk Factors %K Stearic Acids %X

BACKGROUND: Not much is known about the relations of circulating saturated fatty acids (SFAs), which are influenced by both metabolic and dietary determinants, with total and cause-specific mortality.

OBJECTIVE: We examined the associations of plasma phospholipid SFAs with total and cause-specific mortality among 3941 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged ≥65 y who were followed from 1992 through 2011.

METHODS: The relations of total and cause-specific mortality with plasma phospholipid palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) were assessed using Cox proportional hazards models.

RESULTS: During 45,450 person-years of follow-up, 3134 deaths occurred. Higher concentrations of the plasma phospholipid SFAs 18:0, 22:0, and 24:0 were associated with a lower risk of total mortality [multivariable-adjusted HRs (95% CIs)] for the top compared with the bottom quintile: 0.85 (0.75, 0.95) for 18:0; 0.85 (0.75, 0.95) for 22:0; and 0.80 (0.71, 0.90) for 24:0. In contrast, plasma 16:0 concentrations in the highest quintile were associated with a higher risk of total mortality compared with concentrations in the lowest quintile [1.25 (1.11, 1.41)]. We also found no association of plasma phospholipid 20:0 with total mortality.

CONCLUSIONS: These findings suggest that the associations of plasma phospholipid SFAs with the risk of death differ according to SFA chain length and support future studies to better characterize the determinants of circulating SFAs and to explore the mechanisms underlying these relations.

%B J Nutr %V 146 %P 298-305 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26701797?dopt=Abstract %R 10.3945/jn.115.222117 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T Genetic Variants Associated with Circulating Parathyroid Hormone. %A Robinson-Cohen, Cassianne %A Lutsey, Pamela L %A Kleber, Marcus E %A Nielson, Carrie M %A Mitchell, Braxton D %A Bis, Joshua C %A Eny, Karen M %A Portas, Laura %A Eriksson, Joel %A Lorentzon, Mattias %A Koller, Daniel L %A Milaneschi, Yuri %A Teumer, Alexander %A Pilz, Stefan %A Nethander, Maria %A Selvin, Elizabeth %A Tang, Weihong %A Weng, Lu-Chen %A Wong, Hoi Suen %A Lai, Dongbing %A Peacock, Munro %A Hannemann, Anke %A Völker, Uwe %A Homuth, Georg %A Nauk, Matthias %A Murgia, Federico %A Pattee, Jack W %A Orwoll, Eric %A Zmuda, Joseph M %A Riancho, Jose Antonio %A Wolf, Myles %A Williams, Frances %A Penninx, Brenda %A Econs, Michael J %A Ryan, Kathleen A %A Ohlsson, Claes %A Paterson, Andrew D %A Psaty, Bruce M %A Siscovick, David S %A Rotter, Jerome I %A Pirastu, Mario %A Streeten, Elizabeth %A März, Winfried %A Fox, Caroline %A Coresh, Josef %A Wallaschofski, Henri %A Pankow, James S %A de Boer, Ian H %A Kestenbaum, Bryan %X

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 × 10(-16)), rs4443100 near RTDR1 (P=8.7 × 10(-9)), and rs73186030 near CASR (P=4.8 × 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

%B J Am Soc Nephrol %8 2016 Dec 07 %G eng %R 10.1681/ASN.2016010069 %0 Journal Article %J PLoS One %D 2016 %T Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. %A Dehghan, Abbas %A Bis, Joshua C %A White, Charles C %A Smith, Albert Vernon %A Morrison, Alanna C %A Cupples, L Adrienne %A Trompet, Stella %A Chasman, Daniel I %A Lumley, Thomas %A Völker, Uwe %A Buckley, Brendan M %A Ding, Jingzhong %A Jensen, Majken K %A Folsom, Aaron R %A Kritchevsky, Stephen B %A Girman, Cynthia J %A Ford, Ian %A Dörr, Marcus %A Salomaa, Veikko %A Uitterlinden, André G %A Eiriksdottir, Gudny %A Vasan, Ramachandran S %A Franceschini, Nora %A Carty, Cara L %A Virtamo, Jarmo %A Demissie, Serkalem %A Amouyel, Philippe %A Arveiler, Dominique %A Heckbert, Susan R %A Ferrieres, Jean %A Ducimetiere, Pierre %A Smith, Nicholas L %A Wang, Ying A %A Siscovick, David S %A Rice, Kenneth M %A Wiklund, Per-Gunnar %A Taylor, Kent D %A Evans, Alun %A Kee, Frank %A Rotter, Jerome I %A Karvanen, Juha %A Kuulasmaa, Kari %A Heiss, Gerardo %A Kraft, Peter %A Launer, Lenore J %A Hofman, Albert %A Markus, Marcello R P %A Rose, Lynda M %A Silander, Kaisa %A Wagner, Peter %A Benjamin, Emelia J %A Lohman, Kurt %A Stott, David J %A Rivadeneira, Fernando %A Harris, Tamara B %A Levy, Daniel %A Liu, Yongmei %A Rimm, Eric B %A Jukema, J Wouter %A Völzke, Henry %A Ridker, Paul M %A Blankenberg, Stefan %A Franco, Oscar H %A Gudnason, Vilmundur %A Psaty, Bruce M %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Aged %K Cohort Studies %K Cooperative Behavior %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

%B PLoS One %V 11 %P e0144997 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract %R 10.1371/journal.pone.0144997 %0 Journal Article %J Diabetes %D 2016 %T Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. %A Walford, Geoffrey A %A Gustafsson, Stefan %A Rybin, Denis %A Stančáková, Alena %A Chen, Han %A Liu, Ching-Ti %A Hong, Jaeyoung %A Jensen, Richard A %A Rice, Ken %A Morris, Andrew P %A Mägi, Reedik %A Tönjes, Anke %A Prokopenko, Inga %A Kleber, Marcus E %A Delgado, Graciela %A Silbernagel, Günther %A Jackson, Anne U %A Appel, Emil V %A Grarup, Niels %A Lewis, Joshua P %A Montasser, May E %A Landenvall, Claes %A Staiger, Harald %A Luan, Jian'an %A Frayling, Timothy M %A Weedon, Michael N %A Xie, Weijia %A Morcillo, Sonsoles %A Martínez-Larrad, María Teresa %A Biggs, Mary L %A Chen, Yii-Der Ida %A Corbaton-Anchuelo, Arturo %A Færch, Kristine %A Gómez-Zumaquero, Juan Miguel %A Goodarzi, Mark O %A Kizer, Jorge R %A Koistinen, Heikki A %A Leong, Aaron %A Lind, Lars %A Lindgren, Cecilia %A Machicao, Fausto %A Manning, Alisa K %A Martín-Núñez, Gracia María %A Rojo-Martínez, Gemma %A Rotter, Jerome I %A Siscovick, David S %A Zmuda, Joseph M %A Zhang, Zhongyang %A Serrano-Ríos, Manuel %A Smith, Ulf %A Soriguer, Federico %A Hansen, Torben %A Jørgensen, Torben J %A Linnenberg, Allan %A Pedersen, Oluf %A Walker, Mark %A Langenberg, Claudia %A Scott, Robert A %A Wareham, Nicholas J %A Fritsche, Andreas %A Häring, Hans-Ulrich %A Stefan, Norbert %A Groop, Leif %A O'Connell, Jeff R %A Boehnke, Michael %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A März, Winfried %A Kovacs, Peter %A Stumvoll, Michael %A Psaty, Bruce M %A Kuusisto, Johanna %A Laakso, Markku %A Meigs, James B %A Dupuis, Josée %A Ingelsson, Erik %A Florez, Jose C %X

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

%B Diabetes %V 65 %P 3200-11 %8 2016 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/27416945?dopt=Abstract %R 10.2337/db16-0199 %0 Journal Article %J Circulation %D 2016 %T Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. %A Waks, Jonathan W %A Sitlani, Colleen M %A Soliman, Elsayed Z %A Kabir, Muammar %A Ghafoori, Elyar %A Biggs, Mary L %A Henrikson, Charles A %A Sotoodehnia, Nona %A Biering-Sørensen, Tor %A Agarwal, Sunil K %A Siscovick, David S %A Post, Wendy S %A Solomon, Scott D %A Buxton, Alfred E %A Josephson, Mark E %A Tereshchenko, Larisa G %X

BACKGROUND: Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary.

METHODS AND RESULTS: Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44-100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%.

CONCLUSIONS: Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.

%B Circulation %V 133 %P 2222-34 %8 2016 Jun 7 %G eng %N 23 %R 10.1161/CIRCULATIONAHA.116.021306 %0 Journal Article %J J Am Geriatr Soc %D 2016 %T Incident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study. %A Wallace, Erin R %A Siscovick, David S %A Sitlani, Colleen M %A Dublin, Sascha %A Mitchell, Pamela H %A Odden, Michelle C %A Hirsch, Calvin H %A Thielke, Stephen %A Heckbert, Susan R %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Disability Evaluation %K Electrocardiography %K Female %K Geriatric Assessment %K Humans %K Incidence %K Longevity %K Longitudinal Studies %K Male %K Medicare %K Prevalence %K Prospective Studies %K Survival Rate %K United States %X

OBJECTIVES: To assess the associations between incident atrial fibrillation (AF) and disability-free survival and risk of disability.

DESIGN: Prospective cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older and enrolled in fee-for-service Medicare followed between 1991 and 2009 (MN = 4,046). Individuals with prevalent AF, activity of daily living (ADL) disability, or a history of stroke or heart failure at baseline were excluded.

MEASUREMENTS: Incident AF was identified according to annual study electrocardiogram, hospital discharge diagnosis, or Medicare claims. Disability-free survival was defined as survival free of ADL disability (any difficulty or inability in bathing, dressing, eating, using the toilet, walking around the home, or getting out of a bed or chair). ADLs were assessed at annual study visits or in a telephone interview. Association between incident AF and disability-free survival or risk of disability was estimated using Cox proportional hazards models.

RESULTS: Over an average of 7.0 years of follow-up, 660 individuals (16.3%) developed incident AF, and 3,112 (77%) became disabled or died. Incident AF was associated with shorter disability-free survival (hazard ratio (HR) for death or ADL disability = 1.71, 95% confidence interval (CI) = 1.55-1.90) and a higher risk of ADL disability (HR = 1.36, 95% CI = 1.18-1.58) than in individuals with no history of AF. This association persisted after adjustment for interim stroke and heart failure.

CONCLUSION: These results suggest that AF is a risk factor for shorter functional longevity in older adults, independent of other risk factors and comorbid conditions.

%B J Am Geriatr Soc %V 64 %P 838-43 %8 2016 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26926559?dopt=Abstract %R 10.1111/jgs.14037 %0 Journal Article %J Am J Clin Nutr %D 2016 %T Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Ma, Yiyi %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Manichaikul, Ani W %A Chu, Audrey Y %A Samieri, Cecilia %A Zhou, Xia %A Guan, Weihua %A Wang, Lu %A Biggs, Mary L %A Chen, Yii-der I %A Hernandez, Dena G %A Borecki, Ingrid %A Chasman, Daniel I %A Rich, Stephen S %A Ferrucci, Luigi %A Irvin, Marguerite Ryan %A Aslibekyan, Stella %A Zhi, Degui %A Tiwari, Hemant K %A Claas, Steven A %A Sha, Jin %A Kabagambe, Edmond K %A Lai, Chao-Qiang %A Parnell, Laurence D %A Lee, Yu-Chi %A Amouyel, Philippe %A Lambert, Jean-Charles %A Psaty, Bruce M %A King, Irena B %A Mozaffarian, Dariush %A McKnight, Barbara %A Bandinelli, Stefania %A Tsai, Michael Y %A Ridker, Paul M %A Ding, Jingzhong %A Mstat, Kurt Lohmant %A Liu, Yongmei %A Sotoodehnia, Nona %A Barberger-Gateau, Pascale %A Steffen, Lyn M %A Siscovick, David S %A Absher, Devin %A Arnett, Donna K %A Ordovas, Jose M %A Lemaitre, Rozenn N %K Apolipoproteins E %K ATP Binding Cassette Transporter 1 %K Cholesterol, HDL %K Cohort Studies %K Diet %K DNA Methylation %K Eicosapentaenoic Acid %K Epigenesis, Genetic %K Fatty Acids %K Gene Expression Regulation %K Humans %K Lipids %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Triglycerides %X

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

%B Am J Clin Nutr %V 103 %P 567-78 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26791180?dopt=Abstract %R 10.3945/ajcn.115.112987 %0 Journal Article %J Metabolism %D 2016 %T Longitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study. %A Brutsaert, Erika F %A Biggs, Mary L %A Delaney, Joseph A %A Djoussé, Luc %A Gottdiener, John S %A Ix, Joachim H %A Kim, Francis %A Mukamal, Kenneth J %A Siscovick, David S %A Tracy, Russell P %A de Boer, Ian H %A deFilippi, Christopher R %A Kizer, Jorge R %X

INTRODUCTION: Natriuretic peptides have a well-recognized role in cardiovascular homeostasis. Recently, higher levels of B-type natriuretic peptide (BNP) have also been associated with decreased risk of diabetes in middle-aged adults. Whether this association persists into older age, where the pathophysiology of diabetes changes, has not been established, nor has its intermediate pathways.

METHODS: We investigated the relationship between N-terminal (NT)-proBNP and incident diabetes in 2359 older adults free of cardiovascular disease or chronic kidney disease in the Cardiovascular Health Study.

RESULTS: We documented 348 incident cases of diabetes over 12.6years of median follow-up. After adjusting for age, sex, race, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL, each doubling of NT-proBNP was associated with a 9% lower risk of incident diabetes (HR=0.91 [95% CI: 0.84-0.99]). Additional adjustment for waist circumference, physical activity, estimated glomerular filtration rate or C-reactive protein did not influence the association. Among putative mediators, HDL and triglycerides, adiponectin, and especially homeostasis model assessment of insulin resistance, all appeared to account for a portion of the lower risk associated with NT-proBNP.

CONCLUSION: In older adults without prevalent cardiovascular or kidney disease, higher NT-proBNP is associated with decreased risk of incident diabetes even after adjustment for traditional risk factors. These findings suggest that the metabolic effects of natriuretic peptides persist late in life and offer a potential therapeutic target for prevention of diabetes in older people.

%B Metabolism %V 65 %P 1489-97 %8 2016 Oct %G eng %N 10 %R 10.1016/j.metabol.2016.06.002 %0 Journal Article %J Am J Epidemiol %D 2016 %T Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study. %A Karas, Maria G %A Yee, Laura M %A Biggs, Mary L %A Djoussé, Luc %A Mukamal, Kenneth J %A Ix, Joachim H %A Zieman, Susan J %A Siscovick, David S %A Gottdiener, John S %A Rosenberg, Michael A %A Kronmal, Richard A %A Heckbert, Susan R %A Kizer, Jorge R %X

Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.

%B Am J Epidemiol %V 183 %P 998-1007 %8 2016 Jun 1 %G eng %N 11 %R 10.1093/aje/kwv278 %0 Journal Article %J Circulation %D 2016 %T Physical Activity and Risk of Coronary Heart Disease and Stroke in Older Adults: The Cardiovascular Health Study. %A Soares-Miranda, Luisa %A Siscovick, David S %A Psaty, Bruce M %A Longstreth, W T %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Coronary Disease %K Female %K Follow-Up Studies %K Health Status %K Humans %K Leisure Activities %K Male %K Motor Activity %K Proportional Hazards Models %K Prospective Studies %K Sampling Studies %K Stroke %K United States %K Walking %X

BACKGROUND: Although guidelines suggest that older adults engage in regular physical activity (PA) to reduce cardiovascular disease (CVD), surprisingly few studies have evaluated this relationship, especially in those >75 years. In addition, with advancing age the ability to perform some types of PA might decrease, making light-moderate exercise such as walking especially important to meet recommendations.

METHODS AND RESULTS: Prospective cohort analysis among 4207 US men and women of a mean age of 73 years (standard deviation=6) who were free of CVD at baseline in the Cardiovascular Health Study were followed from 1989 to 1999. PA was assessed and cumulatively updated over time to minimize misclassification and assess the long-term effects of habitual activity. Walking (pace, blocks, combined walking score) was updated annually from baseline through 1999. Leisure-time activity and exercise intensity were updated at baseline, 1992, and 1996. Incident CVD (fatal or nonfatal myocardial infarction, coronary death, or stroke) was adjudicated using medical records. During 41,995 person-years of follow-up, 1182 CVD events occurred. After multivariable adjustment, greater PA was inversely associated with coronary heart disease, stroke (especially ischemic stroke), and total CVD, even in those ≥75 years. Walking pace, distance, and overall walking score, leisure-time activity, and exercise intensity were each associated with lower risk. For example, in comparison with a walking pace <2 mph, those that habitually walked at a pace >3 mph had a lower risk of coronary heart disease (0.50; confidence interval, 0.38-0.67), stroke (0.47; confidence interval, 033-0.66), and CVD (0.50; confidence interval, 0.40-0.62).

CONCLUSIONS: These data provide empirical evidence supporting PA recommendations, in particular, walking, to reduce the incidence of CVD among older adults.

%B Circulation %V 133 %P 147-55 %8 2016 Jan 12 %G ENG %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26538582?dopt=Abstract %R 10.1161/CIRCULATIONAHA.115.018323 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2016 %T Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study. %A Brutsaert, Erika F %A Shitole, Sanyog %A Biggs, Mary Lou %A Mukamal, Kenneth J %A deBoer, Ian H %A Thacker, Evan L %A Barzilay, Joshua I %A Djoussé, Luc %A Ix, Joachim H %A Smith, Nicholas L %A Kaplan, Robert C %A Siscovick, David S %A Psaty, Bruce M %A Kizer, Jorge R %K Aged %K Aging %K Blood Glucose %K Cardiovascular Diseases %K Fasting %K Female %K Follow-Up Studies %K Glucose %K Glucose Tolerance Test %K Health Surveys %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Survival Rate %K United States %X

BACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse.

METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic.

RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models.

CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.

%B J Gerontol A Biol Sci Med Sci %V 71 %P 370-7 %8 2016 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26314953?dopt=Abstract %R 10.1093/gerona/glv106 %0 Journal Article %J J Clin Endocrinol Metab %D 2016 %T Testosterone, Dihydrotestosterone, Sex Hormone Binding Globulin and Incident Diabetes among Older Men: the Cardiovascular Health Study. %A Joyce, Katherine E %A Biggs, Mary L %A Djoussé, Luc %A Ix, Joachim H %A Kizer, Jorge R %A Siscovick, David S %A Shores, Molly M %A Matsumoto, Alvin M %A Mukamal, Kenneth J %X

CONTEXT: Although sex hormone binding globulin (SHBG) and testosterone (T) have been inversely associated with risk of diabetes, few studies have examined dihydrotestosterone (DHT), a more potent androgen than T, or older adults, whose glycemic pathophysiology differs from younger adults.

OBJECTIVE: To determine the associations of SHBG, T, and DHT with insulin resistance and incident diabetes in older adult men.

DESIGN: In a prospective cohort study, we evaluated baseline levels of SHBG, T, and DHT using liquid chromatography-tandem mass spectrometry among 852 men in the Cardiovascular Health Study free of diabetes and cardiovascular disease in 1994.

MAIN OUTCOME: Insulin resistance estimated by HOMA-IR and insulin sensitivity estimated by the Gutt index in 1996, and incident diabetes (n=112) ascertained over a mean follow-up of 9.8 years.

RESULTS: In linear regression models adjusted for demographics, alcohol consumption, current smoking, body-mass index, and other androgens, SHBG (HOMA-IR 0.30 units lower per doubling; 95% confidence interval [CI], 0.08-0.52; p=0.01) and total DHT (HOMA-IR 0.18 units lower per doubling; 95% CI 0.06-0.30; p=0.01), but not free T (p=0.33) were inversely associated with insulin resistance. In corresponding Cox proportional hazards models, total DHT was again inversely associated with risk of diabetes (adjusted hazard ratio per doubling 0.69; 95% CI, 0.52-0.92; p=0.01), but SHBG (hazard ratio 1.09; 95% CI, 0.74-1.59; p=0.66) and free T (hazard ratio 1.15; 95% CI, 0.92-1.43; p=0.23) were not.

CONCLUSIONS: Among older men, higher levels of DHT are inversely associated with insulin resistance and risk of diabetes over the ensuing 10 years, while levels of T are not. Future studies are still needed to clarify the role of SHBG in risk of diabetes in this population.

%B J Clin Endocrinol Metab %P jc20162623 %8 2016 Oct 12 %G eng %R 10.1210/jc.2016-2623 %0 Journal Article %J Am J Hum Genet %D 2016 %T Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. %A Liu, Ching-Ti %A Raghavan, Sridharan %A Maruthur, Nisa %A Kabagambe, Edmond Kato %A Hong, Jaeyoung %A Ng, Maggie C Y %A Hivert, Marie-France %A Lu, Yingchang %A An, Ping %A Bentley, Amy R %A Drolet, Anne M %A Gaulton, Kyle J %A Guo, Xiuqing %A Armstrong, Loren L %A Irvin, Marguerite R %A Li, Man %A Lipovich, Leonard %A Rybin, Denis V %A Taylor, Kent D %A Agyemang, Charles %A Palmer, Nicholette D %A Cade, Brian E %A Chen, Wei-Min %A Dauriz, Marco %A Delaney, Joseph A C %A Edwards, Todd L %A Evans, Daniel S %A Evans, Michele K %A Lange, Leslie A %A Leong, Aaron %A Liu, Jingmin %A Liu, Yongmei %A Nayak, Uma %A Patel, Sanjay R %A Porneala, Bianca C %A Rasmussen-Torvik, Laura J %A Snijder, Marieke B %A Stallings, Sarah C %A Tanaka, Toshiko %A Yanek, Lisa R %A Zhao, Wei %A Becker, Diane M %A Bielak, Lawrence F %A Biggs, Mary L %A Bottinger, Erwin P %A Bowden, Donald W %A Chen, Guanjie %A Correa, Adolfo %A Couper, David J %A Crawford, Dana C %A Cushman, Mary %A Eicher, John D %A Fornage, Myriam %A Franceschini, Nora %A Fu, Yi-Ping %A Goodarzi, Mark O %A Gottesman, Omri %A Hara, Kazuo %A Harris, Tamara B %A Jensen, Richard A %A Johnson, Andrew D %A Jhun, Min A %A Karter, Andrew J %A Keller, Margaux F %A Kho, Abel N %A Kizer, Jorge R %A Krauss, Ronald M %A Langefeld, Carl D %A Li, Xiaohui %A Liang, Jingling %A Liu, Simin %A Lowe, William L %A Mosley, Thomas H %A North, Kari E %A Pacheco, Jennifer A %A Peyser, Patricia A %A Patrick, Alan L %A Rice, Kenneth M %A Selvin, Elizabeth %A Sims, Mario %A Smith, Jennifer A %A Tajuddin, Salman M %A Vaidya, Dhananjay %A Wren, Mary P %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Julie T %A Zmuda, Joseph M %A Zonderman, Alan B %A Zwinderman, Aeilko H %A Adeyemo, Adebowale %A Boerwinkle, Eric %A Ferrucci, Luigi %A Hayes, M Geoffrey %A Kardia, Sharon L R %A Miljkovic, Iva %A Pankow, James S %A Rotimi, Charles N %A Sale, Michèle M %A Wagenknecht, Lynne E %A Arnett, Donna K %A Chen, Yii-Der Ida %A Nalls, Michael A %A Province, Michael A %A Kao, W H Linda %A Siscovick, David S %A Psaty, Bruce M %A Wilson, James G %A Loos, Ruth J F %A Dupuis, Josée %A Rich, Stephen S %A Florez, Jose C %A Rotter, Jerome I %A Morris, Andrew P %A Meigs, James B %X

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

%B Am J Hum Genet %V 99 %P 56-75 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract %R 10.1016/j.ajhg.2016.05.006 %0 Journal Article %J JAMA Cardiol %D 2017 %T Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies. %A Bansal, Nisha %A Katz, Ronit %A Robinson-Cohen, Cassianne %A Odden, Michelle C %A Dalrymple, Lorien %A Shlipak, Michael G %A Sarnak, Mark J %A Siscovick, David S %A Zelnick, Leila %A Psaty, Bruce M %A Kestenbaum, Bryan %A Correa, Adolfo %A Afkarian, Maryam %A Young, Bessie %A de Boer, Ian H %X

Importance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.

Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.

Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.

Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation.

Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.

Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.

Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.

%B JAMA Cardiol %V 2 %P 314-318 %8 2017 Mar 01 %G eng %N 3 %R 10.1001/jamacardio.2016.4652 %0 Journal Article %J Hum Mol Genet %D 2017 %T Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium. %A Jensen, Majken K %A Jensen, Richard A %A Mukamal, Kenneth J %A Guo, Xiuqing %A Yao, Jie %A Sun, Qi %A Cornelis, Marilyn %A Liu, Yongmei %A Chen, Ming-Huei %A Kizer, Jorge R %A Djoussé, Luc %A Siscovick, David S %A Psaty, Bruce M %A Zmuda, Joseph M %A Rotter, Jerome I %A Garcia, Melissa %A Harris, Tamara %A Chen, Ida %A Goodarzi, Mark O %A Nalls, Michael A %A Keller, Margaux %A Arnold, Alice M %A Newman, Anne %A Hoogeeven, Ron C %A Rexrode, Kathryn M %A Rimm, Eric B %A Hu, Frank B %A Vasan, Ramachandran S %A Katz, Ronit %A Pankow, James S %A Ix, Joachim H %X

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

%B Hum Mol Genet %8 2017 Apr 03 %G eng %R 10.1093/hmg/ddx091 %0 Journal Article %J PLoS Genet %D 2017 %T Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium. %A Ng, Maggie C Y %A Graff, Mariaelisa %A Lu, Yingchang %A Justice, Anne E %A Mudgal, Poorva %A Liu, Ching-Ti %A Young, Kristin %A Yanek, Lisa R %A Feitosa, Mary F %A Wojczynski, Mary K %A Rand, Kristin %A Brody, Jennifer A %A Cade, Brian E %A Dimitrov, Latchezar %A Duan, Qing %A Guo, Xiuqing %A Lange, Leslie A %A Nalls, Michael A %A Okut, Hayrettin %A Tajuddin, Salman M %A Tayo, Bamidele O %A Vedantam, Sailaja %A Bradfield, Jonathan P %A Chen, Guanjie %A Chen, Wei-Min %A Chesi, Alessandra %A Irvin, Marguerite R %A Padhukasahasram, Badri %A Smith, Jennifer A %A Zheng, Wei %A Allison, Matthew A %A Ambrosone, Christine B %A Bandera, Elisa V %A Bartz, Traci M %A Berndt, Sonja I %A Bernstein, Leslie %A Blot, William J %A Bottinger, Erwin P %A Carpten, John %A Chanock, Stephen J %A Chen, Yii-Der Ida %A Conti, David V %A Cooper, Richard S %A Fornage, Myriam %A Freedman, Barry I %A Garcia, Melissa %A Goodman, Phyllis J %A Hsu, Yu-Han H %A Hu, Jennifer %A Huff, Chad D %A Ingles, Sue A %A John, Esther M %A Kittles, Rick %A Klein, Eric %A Li, Jin %A McKnight, Barbara %A Nayak, Uma %A Nemesure, Barbara %A Ogunniyi, Adesola %A Olshan, Andrew %A Press, Michael F %A Rohde, Rebecca %A Rybicki, Benjamin A %A Salako, Babatunde %A Sanderson, Maureen %A Shao, Yaming %A Siscovick, David S %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Vaidya, Dhananjay %A Witte, John S %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Zonderman, Alan B %A Adeyemo, Adebowale %A Ambs, Stefan %A Cushman, Mary %A Faul, Jessica D %A Hakonarson, Hakon %A Levin, Albert M %A Nathanson, Katherine L %A Ware, Erin B %A Weir, David R %A Zhao, Wei %A Zhi, Degui %A Arnett, Donna K %A Grant, Struan F A %A Kardia, Sharon L R %A Oloapde, Olufunmilayo I %A Rao, D C %A Rotimi, Charles N %A Sale, Michèle M %A Williams, L Keoki %A Zemel, Babette S %A Becker, Diane M %A Borecki, Ingrid B %A Evans, Michele K %A Harris, Tamara B %A Hirschhorn, Joel N %A Li, Yun %A Patel, Sanjay R %A Psaty, Bruce M %A Rotter, Jerome I %A Wilson, James G %A Bowden, Donald W %A Cupples, L Adrienne %A Haiman, Christopher A %A Loos, Ruth J F %A North, Kari E %X

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

%B PLoS Genet %V 13 %P e1006719 %8 2017 Apr 21 %G eng %N 4 %R 10.1371/journal.pgen.1006719 %0 Journal Article %J J Lipid Res %D 2017 %T Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations. %A Hu, Yao %A Tanaka, Toshiko %A Zhu, Jingwen %A Guan, Weihua %A Wu, Jason H Y %A Psaty, Bruce M %A McKnight, Barbara %A King, Irena B %A Sun, Qi %A Richard, Melissa %A Manichaikul, Ani %A Frazier-Wood, Alexis C %A Kabagambe, Edmond K %A Hopkins, Paul N %A Ordovas, Jose M %A Ferrucci, Luigi %A Bandinelli, Stefania %A Arnett, Donna K %A Chen, Yii-der I %A Liang, Shuang %A Siscovick, David S %A Tsai, Michael Y %A Rich, Stephen S %A Fornage, Myriam %A Hu, Frank B %A Rimm, Eric B %A Jensen, Majken K %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %A Steffen, Lyn M %A Morris, Andrew P %A Li, Huaixing %A Lin, Xu %X

Monounsaturated fatty acids (MUFAs) are unsaturated fatty acids with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels were associated with cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). Previous genome-wide association studies (GWAS) have identified seven loci for plasma and erythrocyte palmitoleic acid and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential causal variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in over 15,000 participants of Chinese- and European-ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor)>=8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor)>=61619;6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering ~95kb) to five (covering ~20kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were enriched in unsaturated fatty acids metabolism and signaling pathways. Our findings provided novel insight into the genetic basis relevant to MUFA metabolism and biology.

%B J Lipid Res %8 2017 Mar 15 %G eng %R 10.1194/jlr.P071860 %0 Journal Article %J Mol Nutr Food Res %D 2017 %T Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent. %A Smith, Caren E %A Follis, Jack L %A Dashti, Hassan S %A Tanaka, Toshiko %A Graff, Mariaelisa %A Fretts, Amanda M %A Kilpeläinen, Tuomas O %A Wojczynski, Mary K %A Richardson, Kris %A Nalls, Mike A %A Schulz, Christina-Alexandra %A Liu, Yongmei %A Frazier-Wood, Alexis C %A van Eekelen, Esther %A Wang, Carol %A de Vries, Paul S %A Mikkilä, Vera %A Rohde, Rebecca %A Psaty, Bruce M %A Hansen, Torben %A Feitosa, Mary F %A Lai, Chao-Qiang %A Houston, Denise K %A Ferruci, Luigi %A Ericson, Ulrika %A Wang, Zhe %A de Mutsert, Renée %A Oddy, Wendy H %A de Jonge, Ester A L %A Seppälä, Ilkka %A Justice, Anne E %A Lemaitre, Rozenn N %A Sørensen, Thorkild I A %A Province, Michael A %A Parnell, Laurence D %A Garcia, Melissa E %A Bandinelli, Stefania %A Orho-Melander, Marju %A Rich, Stephen S %A Rosendaal, Frits R %A Pennell, Craig E %A Kiefte-de Jong, Jessica C %A Kähönen, Mika %A Young, Kristin L %A Pedersen, Oluf %A Aslibekyan, Stella %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Zillikens, M Carola %A Raitakari, Olli T %A North, Kari E %A Overvad, Kim %A Arnett, Donna K %A Hofman, Albert %A Lehtimäki, Terho %A Tjønneland, Anne %A Uitterlinden, André G %A Rivadeneira, Fernando %A Franco, Oscar H %A German, J Bruce %A Siscovick, David S %A Cupples, L Adrienne %A Ordovas, Jose M %X

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

%B Mol Nutr Food Res %8 2017 Sep 21 %G eng %R 10.1002/mnfr.201700347 %0 Journal Article %J PLoS Med %D 2017 %T Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. %A Wheeler, Eleanor %A Leong, Aaron %A Liu, Ching-Ti %A Hivert, Marie-France %A Strawbridge, Rona J %A Podmore, Clara %A Li, Man %A Yao, Jie %A Sim, Xueling %A Hong, Jaeyoung %A Chu, Audrey Y %A Zhang, Weihua %A Wang, Xu %A Chen, Peng %A Maruthur, Nisa M %A Porneala, Bianca C %A Sharp, Stephen J %A Jia, Yucheng %A Kabagambe, Edmond K %A Chang, Li-Ching %A Chen, Wei-Min %A Elks, Cathy E %A Evans, Daniel S %A Fan, Qiao %A Giulianini, Franco %A Go, Min Jin %A Hottenga, Jouke-Jan %A Hu, Yao %A Jackson, Anne U %A Kanoni, Stavroula %A Kim, Young Jin %A Kleber, Marcus E %A Ladenvall, Claes %A Lecoeur, Cécile %A Lim, Sing-Hui %A Lu, Yingchang %A Mahajan, Anubha %A Marzi, Carola %A Nalls, Mike A %A Navarro, Pau %A Nolte, Ilja M %A Rose, Lynda M %A Rybin, Denis V %A Sanna, Serena %A Shi, Yuan %A Stram, Daniel O %A Takeuchi, Fumihiko %A Tan, Shu Pei %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Wong, Andrew %A Yengo, Loic %A Zhao, Wanting %A Goel, Anuj %A Martinez Larrad, Maria Teresa %A Radke, Dörte %A Salo, Perttu %A Tanaka, Toshiko %A van Iperen, Erik P A %A Abecasis, Goncalo %A Afaq, Saima %A Alizadeh, Behrooz Z %A Bertoni, Alain G %A Bonnefond, Amélie %A Böttcher, Yvonne %A Bottinger, Erwin P %A Campbell, Harry %A Carlson, Olga D %A Chen, Chien-Hsiun %A Cho, Yoon Shin %A Garvey, W Timothy %A Gieger, Christian %A Goodarzi, Mark O %A Grallert, Harald %A Hamsten, Anders %A Hartman, Catharina A %A Herder, Christian %A Hsiung, Chao Agnes %A Huang, Jie %A Igase, Michiya %A Isono, Masato %A Katsuya, Tomohiro %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kohara, Katsuhiko %A Kovacs, Peter %A Lee, Juyoung %A Lee, Wen-Jane %A Lehne, Benjamin %A Li, Huaixing %A Liu, Jianjun %A Lobbens, Stephane %A Luan, Jian'an %A Lyssenko, Valeriya %A Meitinger, Thomas %A Miki, Tetsuro %A Miljkovic, Iva %A Moon, Sanghoon %A Mulas, Antonella %A Müller, Gabriele %A Müller-Nurasyid, Martina %A Nagaraja, Ramaiah %A Nauck, Matthias %A Pankow, James S %A Polasek, Ozren %A Prokopenko, Inga %A Ramos, Paula S %A Rasmussen-Torvik, Laura %A Rathmann, Wolfgang %A Rich, Stephen S %A Robertson, Neil R %A Roden, Michael %A Roussel, Ronan %A Rudan, Igor %A Scott, Robert A %A Scott, William R %A Sennblad, Bengt %A Siscovick, David S %A Strauch, Konstantin %A Sun, Liang %A Swertz, Morris %A Tajuddin, Salman M %A Taylor, Kent D %A Teo, Yik-Ying %A Tham, Yih Chung %A Tönjes, Anke %A Wareham, Nicholas J %A Willemsen, Gonneke %A Wilsgaard, Tom %A Hingorani, Aroon D %A Egan, Josephine %A Ferrucci, Luigi %A Hovingh, G Kees %A Jula, Antti %A Kivimaki, Mika %A Kumari, Meena %A Njølstad, Inger %A Palmer, Colin N A %A Serrano Ríos, Manuel %A Stumvoll, Michael %A Watkins, Hugh %A Aung, Tin %A Blüher, Matthias %A Boehnke, Michael %A Boomsma, Dorret I %A Bornstein, Stefan R %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chen, Yduan-Tsong %A Cheng, Ching-Yu %A Cucca, Francesco %A de Geus, Eco J C %A Deloukas, Panos %A Evans, Michele K %A Fornage, Myriam %A Friedlander, Yechiel %A Froguel, Philippe %A Groop, Leif %A Gross, Myron D %A Harris, Tamara B %A Hayward, Caroline %A Heng, Chew-Kiat %A Ingelsson, Erik %A Kato, Norihiro %A Kim, Bong-Jo %A Koh, Woon-Puay %A Kooner, Jaspal S %A Körner, Antje %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lin, Xu %A Liu, Yongmei %A Loos, Ruth J F %A Magnusson, Patrik K E %A März, Winfried %A McCarthy, Mark I %A Oldehinkel, Albertine J %A Ong, Ken K %A Pedersen, Nancy L %A Pereira, Mark A %A Peters, Annette %A Ridker, Paul M %A Sabanayagam, Charumathi %A Sale, Michele %A Saleheen, Danish %A Saltevo, Juha %A Schwarz, Peter Eh %A Sheu, Wayne H H %A Snieder, Harold %A Spector, Timothy D %A Tabara, Yasuharu %A Tuomilehto, Jaakko %A van Dam, Rob M %A Wilson, James G %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wong, Tien Yin %A Wu, Jer-Yuarn %A Yuan, Jian-Min %A Zonderman, Alan B %A Soranzo, Nicole %A Guo, Xiuqing %A Roberts, David J %A Florez, Jose C %A Sladek, Robert %A Dupuis, Josée %A Morris, Andrew P %A Tai, E-Shyong %A Selvin, Elizabeth %A Rotter, Jerome I %A Langenberg, Claudia %A Barroso, Inês %A Meigs, James B %K Diabetes Mellitus, Type 2 %K Genetic Variation %K Genome-Wide Association Study %K Glycated Hemoglobin A %K Humans %K Phenotype %K Risk %X

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

%B PLoS Med %V 14 %P e1002383 %8 2017 Sep %G eng %N 9 %R 10.1371/journal.pmed.1002383 %0 Journal Article %J Clin J Am Soc Nephrol %D 2017 %T The Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals. %A Hughes-Austin, Jan M %A Rifkin, Dena E %A Beben, Tomasz %A Katz, Ronit %A Sarnak, Mark J %A Deo, Rajat %A Hoofnagle, Andrew N %A Homma, Shunichi %A Siscovick, David S %A Sotoodehnia, Nona %A Psaty, Bruce M %A de Boer, Ian H %A Kestenbaum, Bryan %A Shlipak, Michael G %A Ix, Joachim H %X

BACKGROUND AND OBJECTIVES: Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR<60 ml/min per 1.73 m(2) modified these associations.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000-2002 in the MESA and 1989-1993 in the CHS), we investigated associations between serum potassium categories (<3.5, 3.5-3.9, 4.0-4.4, 4.5-4.9, and ≥5.0 mEq/L) and CVD events, mortality, and mortality subtypes (CVD versus non-CVD) using Cox proportional hazards models, adjusting for demographics, time-varying eGFR, traditional CVD risk factors, and use of potassium-altering medications.

RESULTS: Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction<0.02 for all), such that participants who had serum potassium ≥5.0 mEq/L and were concurrently using diuretics were at higher risk of each end point compared with those not using diuretics.

CONCLUSIONS: Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.

%B Clin J Am Soc Nephrol %V 12 %P 245-252 %8 2017 Feb 07 %G eng %N 2 %R 10.2215/CJN.06290616 %0 Journal Article %J Arch Osteoporos %D 2017 %T Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study. %A Massera, Daniele %A Xu, Shuo %A Bartz, Traci M %A Bortnick, Anna E %A Ix, Joachim H %A Chonchol, Michel %A Owens, David S %A Barasch, Eddy %A Gardin, Julius M %A Gottdiener, John S %A Robbins, John R %A Siscovick, David S %A Kizer, Jorge R %X

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found.

INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse.

METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression.

RESULTS: Mean (SD) age was 76.2 (4.8) years; 58% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0%; AAC 45.1 and 46.7%; MAC 42.8 and 39.5%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD = 1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant.

CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

%B Arch Osteoporos %V 12 %P 52 %8 2017 Dec %G eng %N 1 %R 10.1007/s11657-017-0347-y %0 Journal Article %J Biomarkers %D 2017 %T Sleep-disordered breathing is associated with higher carboxymethyllysine level in elderly women but not elderly men in the cardiovascular health study. %A Ahiawodzi, Peter D %A Kerber, Richard A %A Taylor, Kira C %A Groves, Frank D %A O'Brien, Elizabeth %A Ix, Joachim H %A Kizer, Jorge R %A Djoussé, Luc %A Tracy, Russell P %A Newman, Anne B %A Siscovick, David S %A Robbins, John %A Mukamal, Kenneth %X

CONTEXT: Carboxymethyl-lysine (CML) results from oxidative stress and has been linked to cardiovascular disease.

OBJECTIVE: The objective of this study is to investigate the association between sleep-disordered breathing (SDB) - a source of oxidative stress - and CML.

MATERIALS AND METHODS: About 1002 participants in the Cardiovascular Health Study (CHS) were studied.

RESULTS: Women with SDB had significantly higher CML concentration compared with those without SDB (OR = 1.63, 95%CI = 1.03-2.58, p = 0.04). The association was not significant among men.

DISCUSSION: SDB was associated with CML concentration among elderly women but not men in the Cardiovascular Health Study.

CONCLUSION: Accumulation of CML may be an adverse health consequence of SDB.

%B Biomarkers %V 22 %P 361-366 %8 2017 May - Jun %G eng %N 3-4 %R 10.1080/1354750X.2016.1276966 %0 Journal Article %J Diabetes Care %D 2018 %T Biochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study. %A Massera, Daniele %A Biggs, Mary L %A Walker, Marcella D %A Mukamal, Kenneth J %A Ix, Joachim H %A Djoussé, Luc %A Valderrábano, Rodrigo J %A Siscovick, David S %A Tracy, Russell P %A Xue, XiaoNan %A Kizer, Jorge R %X

OBJECTIVE: To investigate the relationship of osteocalcin (OC), a marker of bone formation, and C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone resorption, with incident diabetes in older women.

RESEARCH DESIGN AND METHODS: The analysis included 1,455 female participants from the population-based Cardiovascular Health Study (CHS) (mean [SD] age 74.6 [5.0] years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regression. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models.

RESULTS: OC and CTX were strongly correlated ( = 0.80). In cross-sectional analyses, significant or near-significant inverse associations with HOMA-IR were observed for continuous levels of OC (β = -0.12 per SD increment; = 0.004) and CTX (β = -0.08 per SD; = 0.051) after full adjustment for demographic, lifestyle, and clinical covariates. During a median follow-up of 11.5 years, 196 cases of incident diabetes occurred. After full adjustment, both biomarkers exhibited inverse associations with incident diabetes (OC: hazard ratio 0.85 per SD [95% CI 0.71-1.02; = 0.075]; CTX: 0.82 per SD [0.69-0.98; = 0.031]), associations that were comparable in magnitude and approached or achieved statistical significance.

CONCLUSIONS: In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders.

%B Diabetes Care %V 41 %P 1901-1908 %8 2018 09 %G eng %N 9 %R 10.2337/dc18-0849 %0 Journal Article %J J Am Heart Assoc %D 2018 %T Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study. %A Lemaitre, Rozenn N %A McKnight, Barbara %A Sotoodehnia, Nona %A Fretts, Amanda M %A Qureshi, Waqas T %A Song, Xiaoling %A King, Irena B %A Sitlani, Colleen M %A Siscovick, David S %A Psaty, Bruce M %A Mozaffarian, Dariush %X

Background Circulating very-long-chain saturated fatty acids ( VLSFAs ) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure ( HF ) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time-varying levels of the 3 major circulating VLSFAs , lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person-years among 4249 participants, we identified 1304 cases of incident HF , including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF ( P trend≤0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95% confidence interval, 0.55-0.81) for 24:0, 0.72 (95% confidence interval, 0.60-0.87) for 22:0 and 0.72 (95% confidence interval, 0.59-0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF , including relevant new risk pathways. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00005133.

%B J Am Heart Assoc %V 7 %P e010019 %8 2018 Nov 06 %G eng %N 21 %R 10.1161/JAHA.118.010019 %0 Journal Article %J Eur Heart J %D 2018 %T A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. %A Ashar, Foram N %A Mitchell, Rebecca N %A Albert, Christine M %A Newton-Cheh, Christopher %A Brody, Jennifer A %A Müller-Nurasyid, Martina %A Moes, Anna %A Meitinger, Thomas %A Mak, Angel %A Huikuri, Heikki %A Junttila, M Juhani %A Goyette, Philippe %A Pulit, Sara L %A Pazoki, Raha %A Tanck, Michael W %A Blom, Marieke T %A Zhao, XiaoQing %A Havulinna, Aki S %A Jabbari, Reza %A Glinge, Charlotte %A Tragante, Vinicius %A Escher, Stefan A %A Chakravarti, Aravinda %A Ehret, Georg %A Coresh, Josef %A Li, Man %A Prineas, Ronald J %A Franco, Oscar H %A Kwok, Pui-Yan %A Lumley, Thomas %A Dumas, Florence %A McKnight, Barbara %A Rotter, Jerome I %A Lemaitre, Rozenn N %A Heckbert, Susan R %A O'Donnell, Christopher J %A Hwang, Shih-Jen %A Tardif, Jean-Claude %A VanDenburgh, Martin %A Uitterlinden, André G %A Hofman, Albert %A Stricker, Bruno H C %A de Bakker, Paul I W %A Franks, Paul W %A Jansson, Jan-Håkan %A Asselbergs, Folkert W %A Halushka, Marc K %A Maleszewski, Joseph J %A Tfelt-Hansen, Jacob %A Engstrøm, Thomas %A Salomaa, Veikko %A Virmani, Renu %A Kolodgie, Frank %A Wilde, Arthur A M %A Tan, Hanno L %A Bezzina, Connie R %A Eijgelsheim, Mark %A Rioux, John D %A Jouven, Xavier %A Kääb, Stefan %A Psaty, Bruce M %A Siscovick, David S %A Arking, Dan E %A Sotoodehnia, Nona %X

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

%B Eur Heart J %8 2018 Aug 28 %G eng %R 10.1093/eurheartj/ehy474 %0 Journal Article %J PLoS Med %D 2018 %T Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. %A Imamura, Fumiaki %A Fretts, Amanda %A Marklund, Matti %A Ardisson Korat, Andres V %A Yang, Wei-Sin %A Lankinen, Maria %A Qureshi, Waqas %A Helmer, Catherine %A Chen, Tzu-An %A Wong, Kerry %A Bassett, Julie K %A Murphy, Rachel %A Tintle, Nathan %A Yu, Chaoyu Ian %A Brouwer, Ingeborg A %A Chien, Kuo-Liong %A Frazier-Wood, Alexis C %A Del Gobbo, Liana C %A Djoussé, Luc %A Geleijnse, Johanna M %A Giles, Graham G %A de Goede, Janette %A Gudnason, Vilmundur %A Harris, William S %A Hodge, Allison %A Hu, Frank %A Koulman, Albert %A Laakso, Markku %A Lind, Lars %A Lin, Hung-Ju %A McKnight, Barbara %A Rajaobelina, Kalina %A Riserus, Ulf %A Robinson, Jennifer G %A Samieri, Cecilia %A Siscovick, David S %A Soedamah-Muthu, Sabita S %A Sotoodehnia, Nona %A Sun, Qi %A Tsai, Michael Y %A Uusitupa, Matti %A Wagenknecht, Lynne E %A Wareham, Nick J %A Wu, Jason HY %A Micha, Renata %A Forouhi, Nita G %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %K Aged %K Australia %K Biomarkers %K Dairy Products %K Diabetes Mellitus, Type 2 %K Dietary Fats %K Europe %K Fatty Acids %K Fatty Acids, Monounsaturated %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Prospective Studies %K Sex Factors %K Taiwan %K United States %X

BACKGROUND: We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).

METHODS AND FINDINGS: Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.

CONCLUSIONS: In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

%B PLoS Med %V 15 %P e1002670 %8 2018 10 %G eng %N 10 %R 10.1371/journal.pmed.1002670 %0 Journal Article %J PLoS One %D 2018 %T Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium. %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A Sun, Qi %A King, Irena B %A Wu, Jason H Y %A Manichaikul, Ani %A Rich, Stephen S %A Tsai, Michael Y %A Chen, Y D %A Fornage, Myriam %A Weihua, Guan %A Aslibekyan, Stella %A Irvin, Marguerite R %A Kabagambe, Edmond K %A Arnett, Donna K %A Jensen, Majken K %A McKnight, Barbara %A Psaty, Bruce M %A Steffen, Lyn M %A Smith, Caren E %A Riserus, Ulf %A Lind, Lars %A Hu, Frank B %A Rimm, Eric B %A Siscovick, David S %A Mozaffarian, Dariush %K Fatty Acids %K Genome-Wide Association Study %K Humans %K Introns %K Lactase %K Myosins %K Polymorphism, Single Nucleotide %K Sphingomyelins %K Sphingosine N-Acyltransferase %K Tumor Suppressor Proteins %X

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

%B PLoS One %V 13 %P e0196951 %8 2018 %G eng %N 5 %R 10.1371/journal.pone.0196951 %0 Journal Article %J J Am Heart Assoc %D 2018 %T Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study). %A Tereshchenko, Larisa G %A Sotoodehnia, Nona %A Sitlani, Colleen M %A Ashar, Foram N %A Kabir, Muammar %A Biggs, Mary L %A Morley, Michael P %A Waks, Jonathan W %A Soliman, Elsayed Z %A Buxton, Alfred E %A Biering-Sørensen, Tor %A Solomon, Scott D %A Post, Wendy S %A Cappola, Thomas P %A Siscovick, David S %A Arking, Dan E %X

BACKGROUND: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.

METHODS AND RESULTS: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near ) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; =1.5×10), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; =2.1×10), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; =5.9×10). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near ), 5 (), 11 (11p11.2 region cluster), and 7 (near ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( locus-with ; locus-with ), and atria ( locus-with expression of a long non-coding RNA and ).

CONCLUSIONS: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

%B J Am Heart Assoc %V 7 %8 2018 Apr 05 %G eng %N 8 %R 10.1161/JAHA.117.008160 %0 Journal Article %J J Am Geriatr Soc %D 2018 %T Metabolic Clusters and Outcomes in Older Adults: The Cardiovascular Health Study. %A Mukamal, Kenneth J %A Siscovick, David S %A de Boer, Ian H %A Ix, Joachim H %A Kizer, Jorge R %A Djoussé, Luc %A Fitzpatrick, Annette L %A Tracy, Russell P %A Boyko, Edward J %A Kahn, Steven E %A Arnold, Alice M %K Aged %K Aged, 80 and over %K Blood Glucose %K C-Reactive Protein %K Cardiovascular Diseases %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Humans %K Incidence %K Insulin %K Longitudinal Studies %K Male %K Prospective Studies %K Risk Factors %K United States %X

BACKGROUND/OBJECTIVES: Few studies have the requisite phenotypic information to define metabolic patterns that may inform our understanding of the pathophysiology and consequences of diabetes in older adults. We sought to characterize clusters of older adults on the basis of shared metabolic features.

DESIGN: Population-based prospective cohort study.

SETTING: Four U.S. Cardiovascular Health Study field centers.

PARTICIPANTS: Individuals aged 65 and older taking no glucose-lowering agents (N = 2,231).

MEASUREMENTS: K-means cluster analysis of 11 metabolic parameters (fasting and postload serum glucose and plasma insulin, fasting C-peptide, body mass index, C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), albuminuria, carboxymethyl lysine (an advanced glycation end-product), procollagen III N-terminal propeptide (a fibrotic marker)) and their associations with incident cardiovascular disease, diabetes, disability, and mortality over 8 to 14.5 years of follow-up and with measures of subclinical cardiovascular disease.

RESULTS: A 6-cluster solution provided robust differentiation into distinct, identifiable clusters. Cluster A (n = 739) had the lowest glucose and insulin and highest eGFR and the lowest rates of all outcomes. Cluster B (n = 419) had high glucose and insulin and intermediate rates of most outcomes. Cluster C (n = 118) had the highest insulin. Cluster D (n = 129) had the highest glucose with much lower insulin. Cluster E (n = 314) had the lowest eGFR and highest albuminuria. Cluster F (n = 512) had the highest CRP. Rates of CVD, mortality, and subclinical atherosclerosis were highest in clusters C, D, and E and were similar to rates in participants with treated diabetes. Incidence of disability was highest in Cluster C.

CONCLUSION: Clustering according to metabolic parameters identifies distinct phenotypes that are strongly associated with clinical and functional outcomes, even at advanced age.

%B J Am Geriatr Soc %V 66 %P 289-296 %8 2018 02 %G eng %N 2 %R 10.1111/jgs.15205 %0 Journal Article %J BMJ %D 2018 %T Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study. %A Lai, Heidi Tm %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A McKnight, Barbara %A Song, Xiaoling %A King, Irena B %A Chaves, Paulo Hm %A Odden, Michelle C %A Newman, Anne B %A Siscovick, David S %A Mozaffarian, Dariush %X

OBJECTIVE: To determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing.

DESIGN: Prospective cohort study.

SETTING: Four communities in the United States (Cardiovascular Health Study) from 1992 to 2015.

PARTICIPANTS: 2622 adults with a mean (SD) age of 74.4 (4.8) and with successful healthy ageing at baseline in 1992-93.

EXPOSURE: Cumulative levels of plasma phospholipid n3-PUFAs were measured using gas chromatography in 1992-93, 1998-99, and 2005-06, expressed as percentage of total fatty acids, including α-linolenic acid from plants and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid from seafoood.

MAIN OUTCOME MEASURE: Healthy ageing defined as survival without chronic diseases (ie, cardiovascular disease, cancer, lung disease, and severe chronic kidney disease), the absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Events were centrally adjudicated or determined from medical records and diagnostic tests.

RESULTS: Higher levels of long chain n3-PUFAs were associated with an 18% lower risk (95% confidence interval 7% to 28%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15% (6% to 23%) and 16% (6% to 25%), respectively. α-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95% confidence interval 0.83 to 1.02).

CONCLUSIONS: In older adults, a higher cumulative level of serially measured circulating n3-PUFAs from seafood (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid), eicosapentaenoic acid, and docosapentaenoic acid (but not docosahexaenoic acid from seafood or α-linolenic acid from plants) was associated with a higher likelihood of healthy ageing. These findings support guidelines for increased dietary consumption of n3-PUFAs in older adults.

%B BMJ %V 363 %P k4067 %8 2018 Oct 17 %G eng %R 10.1136/bmj.k4067 %0 Journal Article %J Am J Clin Nutr %D 2018 %T Serial measures of circulating biomarkers of dairy fat and total and cause-specific mortality in older adults: the Cardiovascular Health Study. %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A Song, Xiaoling %A King, Irena B %A Siscovick, David S %A Mozaffarian, Dariush %X

Background: Controversy has emerged about the benefits compared with harms of dairy fat, including concerns over long-term effects. Previous observational studies have assessed self-reported estimates of consumption or a single biomarker measure at baseline, which may lead to suboptimal estimation of true risk.

Objective: The aim of this study was to investigate prospective associations of serial measures of plasma phospholipid fatty acids pentadecanoic (15:0), heptadecanoic (17:0), and trans-palmitoleic (trans-16:1n-7) acids with total mortality, cause-specific mortality, and cardiovascular disease (CVD) risk among older adults.

Design: Among 2907 US adults aged ≥65 y and free of CVD at baseline, circulating fatty acid concentrations were measured serially at baseline, 6 y, and 13 y. Deaths and CVD events were assessed and adjudicated centrally. Prospective associations were assessed by multivariate-adjusted Cox models incorporating time-dependent exposures and covariates.

Results: During 22 y of follow-up, 2428 deaths occurred, including 833 from CVD, 1595 from non-CVD causes, and 1301 incident CVD events. In multivariable models, circulating pentadecanoic, heptadecanoic, and trans-palmitoleic acids were not significantly associated with total mortality, with extreme-quintile HRs of 1.05 for pentadecanoic (95% CI: 0.91, 1.22), 1.07 for heptadecanoic (95% CI: 0.93, 1.23), and 1.05 for trans-palmitoleic (95% CI: 0.91, 1.20) acids. Circulating heptadecanoic acid was associated with lower CVD mortality (extreme-quintile HR: 0.77; 95% CI: 0.61, 0.98), especially stroke mortality, with a 42% lower risk when comparing extreme quintiles of heptadecanoic acid concentrations (HR: 0.58; 95% CI: 0.35, 0.97). In contrast, heptadecanoic acid was associated with a higher risk of non-CVD mortality (HR: 1.27; 95% CI: 1.07, 1.52), which was not clearly related to any single subtype of non-CVD death. No significant associations of pentadecanoic, heptadecanoic, or trans-palmitoleic acids were seen for total incident CVD, coronary heart disease, or stroke.

Conclusions: Long-term exposure to circulating phospholipid pentadecanoic, heptadecanoic, or trans-palmitoleic acids was not significantly associated with total mortality or incident CVD among older adults. High circulating heptadecanoic acid was inversely associated with CVD and stroke mortality and potentially associated with higher risk of non-CVD death.

%B Am J Clin Nutr %8 2018 Jul 11 %G eng %R 10.1093/ajcn/nqy117 %0 Journal Article %J Diabetologia %D 2018 %T Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. %A McKeown, Nicola M %A Dashti, Hassan S %A Ma, Jiantao %A Haslam, Danielle E %A Kiefte-de Jong, Jessica C %A Smith, Caren E %A Tanaka, Toshiko %A Graff, Mariaelisa %A Lemaitre, Rozenn N %A Rybin, Denis %A Sonestedt, Emily %A Frazier-Wood, Alexis C %A Mook-Kanamori, Dennis O %A Li, Yanping %A Wang, Carol A %A Leermakers, Elisabeth T M %A Mikkilä, Vera %A Young, Kristin L %A Mukamal, Kenneth J %A Cupples, L Adrienne %A Schulz, Christina-Alexandra %A Chen, Tzu-An %A Li-Gao, Ruifang %A Huang, Tao %A Oddy, Wendy H %A Raitakari, Olli %A Rice, Kenneth %A Meigs, James B %A Ericson, Ulrika %A Steffen, Lyn M %A Rosendaal, Frits R %A Hofman, Albert %A Kähönen, Mika %A Psaty, Bruce M %A Brunkwall, Louise %A Uitterlinden, André G %A Viikari, Jorma %A Siscovick, David S %A Seppälä, Ilkka %A North, Kari E %A Mozaffarian, Dariush %A Dupuis, Josée %A Orho-Melander, Marju %A Rich, Stephen S %A de Mutsert, Renée %A Qi, Lu %A Pennell, Craig E %A Franco, Oscar H %A Lehtimäki, Terho %A Herman, Mark A %X

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.

METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.

RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant.

CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.

TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).

%B Diabetologia %V 61 %P 317-330 %8 2018 Feb %G eng %N 2 %R 10.1007/s00125-017-4475-0 %0 Journal Article %J Diab Vasc Dis Res %D 2019 %T Advanced glycation end product carboxymethyl-lysine and risk of incident peripheral artery disease in older adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Biggs, Mary L %A Barzilay, Joshua %A Djoussé, Luc %A Hirsch, Calvin %A Ix, Joachim H %A Kizer, Jorge R %A Tracy, Russell P %A Newman, Anne B %A Siscovick, David S %A Mukamal, Kenneth J %X

Carboxymethyl-lysine is an advanced glycation end product that is detectable in the serum. Higher carboxymethyl-lysine levels have been associated with increased risk of coronary heart disease, stroke and cardiovascular mortality. We determined whether high carboxymethyl-lysine levels are also associated with the risk of peripheral artery disease in Cardiovascular Health Study participants who were all aged 65 years and older at baseline. Multivariate Cox proportional hazards models were used to determine the association of baseline carboxymethyl-lysine levels with incident peripheral artery disease in 3267 individuals followed for a median length of 10.0 years. A total of 157 cases of incident peripheral artery disease occurred during follow-up. No significant relationship between carboxymethyl-lysine and risk of peripheral artery disease was found (hazard ratio per standard deviation increment = 1.03; 95% confidence interval = 0.87, 1.23).

%B Diab Vasc Dis Res %P 1479164119847481 %8 2019 May 08 %G eng %R 10.1177/1479164119847481 %0 Journal Article %J Circ Heart Fail %D 2019 %T Plasma Ceramides and Sphingomyelins in Relation to Heart Failure Risk. %A Lemaitre, Rozenn N %A Jensen, Paul N %A Hoofnagle, Andrew %A McKnight, Barbara %A Fretts, Amanda M %A King, Irena B %A Siscovick, David S %A Psaty, Bruce M %A Heckbert, Susan R %A Mozaffarian, Dariush %A Sotoodehnia, Nona %X

BACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelin (SM) precursors, with heart failure have received limited attention.

METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22), and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (hazard ratio for one SD increase:1.25 [95% CI, 1.16-1.36] and 1.28 [1.18-1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (hazard ratio, 0.85 [0.78-0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (hazard ratios, 0.83 [0.77-0.90], 0.81 [0.75-0.88], and 0.83 [0.77-0.90], respectively). No statistically significant interactions with age, sex, black race, body mass index, or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction.

CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005133.

%B Circ Heart Fail %V 12 %P e005708 %8 2019 Jul %G eng %N 7 %R 10.1161/CIRCHEARTFAILURE.118.005708 %0 Journal Article %J J Am Heart Assoc %D 2019 %T Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study. %A Lai, Heidi T M %A de Oliveira Otto, Marcia C %A Lee, Yujin %A Wu, Jason H Y %A Song, Xiaoling %A King, Irena B %A Psaty, Bruce M %A Lemaitre, Rozenn N %A McKnight, Barbara %A Siscovick, David S %A Mozaffarian, Dariush %X

Background Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6 years, and 13 years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13 years, median follow-up (maximum 22.4 years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95% CI=1.08-1.41; and hazard ratio=0.78, 95% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.

%B J Am Heart Assoc %V 8 %P e012881 %8 2019 Nov 19 %G eng %N 22 %R 10.1161/JAHA.119.012881 %0 Journal Article %J Am J Kidney Dis %D 2020 %T The Difference Between Cystatin C and Creatinine-Based Estimated GFR and Incident Frailty: An Analysis of the Cardiovascular Health Study (CHS). %A Potok, O Alison %A Phil, Ronit Katz D %A Bansal, Nisha %A Siscovick, David S %A Odden, Michelle %A Ix, Joachim H %A Shlipak, Michael G %A Rifkin, Dena E %B Am J Kidney Dis %8 2020 Jul 09 %G eng %R 10.1053/j.ajkd.2020.05.018 %0 Journal Article %J J Am Heart Assoc %D 2020 %T Fatty Acid Binding Protein-4 and Risk of Cardiovascular Disease: The Cardiovascular Health Study. %A Egbuche, Obiora %A Biggs, Mary L %A Ix, Joachim H %A Kizer, Jorge R %A Lyles, Mary F %A Siscovick, David S %A Djoussé, Luc %A Mukamal, Kenneth J %X

Background FABP-4 (fatty acid binding protein-4) is a lipid chaperone in adipocytes and has been associated with prognosis in selected clinical populations. We investigated the associations between circulating FABP-4, risk of incident cardiovascular disease (CVD), and risk of CVD mortality among older adults with and without established CVD. Methods and Results In the Cardiovascular Health Study, we measured FABP4 levels in stored specimens from the 1992-993 visit and followed participants for incident CVD if they were free of prevalent CVD at baseline and for CVD mortality through June 2015. We used Cox regression to estimate hazard ratios for incident CVD and CVD mortality per doubling in serum FABP-4 adjusted for age, sex, race, field center, waist circumference, blood pressure, lipids, fasting glucose, and C-reactive protein. Among 4026 participants free of CVD and 681 with prevalent CVD, we documented 1878 cases of incident CVD and 331 CVD deaths, respectively. In adjusted analyses, FABP-4 was modestly associated with risk of incident CVD (mean, 34.24; SD, 18.90; HR, 1.10 per doubling in FABP-4, 95% CI, 1.00-1.21). In contrast, FABP-4 was more clearly associated with risk of CVD mortality among participants without (HR hazard ratio 1.24, 95% CI, 1.10-1.40) or with prevalent CVD (HR hazard ratio 1.57, 95% CI, 1.24-1.98). These associations were not significantly modified by sex, age, and waist circumference. Conclusions Serum FABP-4 is modestly associated with risk of incident CVD even after adjustment for standard risk factors, but more strongly associated with CVD mortality among older adults with and without established CVD.

%B J Am Heart Assoc %V 9 %P e014070 %8 2020 Apr 07 %G eng %N 7 %R 10.1161/JAHA.119.014070 %0 Journal Article %J J Am Heart Assoc %D 2020 %T Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study. %A Jensen, Paul N %A Fretts, Amanda M %A Hoofnagle, Andrew N %A Sitlani, Colleen M %A McKnight, Barbara %A King, Irena B %A Siscovick, David S %A Psaty, Bruce M %A Heckbert, Susan R %A Mozaffarian, Dariush %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow-up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very-long-chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk (ie, per 2-fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59-0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46-0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03-1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18-2.55). Associations were attenuated with adjustment for NT-proBNP (N-terminal pro-B-type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very-long-chain saturated fatty acids were associated with reduced AF risk.

%B J Am Heart Assoc %V 9 %P e012853 %8 2020 Feb 18 %G eng %N 4 %R 10.1161/JAHA.119.012853 %0 Journal Article %J J Am Heart Assoc %D 2020 %T Serial Biomarkers of De Novo Lipogenesis Fatty Acids and Incident Heart Failure in Older Adults: The Cardiovascular Health Study. %A Lee, Yujin %A Lai, Heidi T M %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A McKnight, Barbara %A King, Irena B %A Song, Xiaoling %A Huggins, Gordon S %A Vest, Amanda R %A Siscovick, David S %A Mozaffarian, Dariush %X

Background De novo lipogenesis (DNL) is an endogenous pathway that converts excess dietary starch, sugar, protein, and alcohol into specific fatty acids (FAs). Although elevated DNL is linked to several metabolic abnormalities, little is known about how long-term habitual levels and changes in levels of FAs in the DNL pathway relate to incident heart failure (HF). Methods and Results We investigated whether habitual levels and changes in serial measures of FAs in the DNL pathway were associated with incident HF among 4249 participants free of HF at baseline. Plasma phospholipid FAs were measured at baseline, 6 years, and 13 years using gas chromatography, and risk factors for HF were measured using standardized methods. Incident HF was centrally adjudicated using medical records. We prospectively evaluated associations with HF risk of (1) habitual FA levels, using cumulative updating to assess long-term exposure, and (2) changes in FA levels over time. During 22.1 years of follow-up, 1304 HF cases occurred. After multivariable adjustment, habitual levels and changes in levels of palmitic acid (16:0) were positively associated with incident HF (interquintile hazard ratio [95% CI]=1.17 [1.00-1.36] and 1.26 [1.03-1.55], respectively). Changes in levels of 7-hexadecenoic acid (16:1n-9) and vaccenic acid (18:1n-7) were each positively associated with risk of HF (1.36 [1.13-1.62], and 1.43 [1.18-1.72], respectively). Habitual levels and changes in levels of myristic acid (14:0), palmitoleic acid (16:1n-7), stearic acid (18:0), and oleic acid (18:1n-9) were not associated with incident HF. Conclusions Both habitual levels and changes in levels of 16:0 were positively associated with incident HF in older adults. Changes in 16:1n-9 and 18:1n-7 were also positively associated with incident HF. These findings support a potential role of DNL or these DNL-related FAs in the development of HF.

%B J Am Heart Assoc %V 9 %P e014119 %8 2020 Feb 18 %G eng %N 4 %R 10.1161/JAHA.119.014119 %0 Journal Article %J JAMA Netw Open %D 2021 %T Assessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging. %A Bockus, Lee B %A Biggs, Mary L %A Lai, Heidi T M %A de Olivera Otto, Marcia C %A Fretts, Amanda M %A McKnight, Barbara %A Sotoodehnia, Nona %A King, Irena B %A Song, Xiaoling %A Siscovick, David S %A Mozaffarian, Dariush %A Lemaitre, Rozenn N %X

Importance: Identifying novel factors that protect against age-related diseases and promote healthy aging is critical to public health. Higher levels of circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism shown to have beneficial associations in cardiovascular disease and total mortality, but whether they are associated with overall healthy aging is unknown.

Objective: To examine the association of circulating levels of 3 VLSFAs with unhealthy aging events, including incident chronic disease (cardiovascular disease, cancer, lung disease or severe kidney disease), physical dysfunction, and cognitive decline.

Design, Setting, and Participants: This cohort study used 1992 to 2014 data from the Cardiovascular Health Study (CHS). The CHS is a multicenter, population-based study of cardiovascular disease among older adults. Among the 4559 CHS participants with available fatty acid data, 1879 participants who had an age-related event before their first measurement were excluded. Data analysis was performed in 2020.

Main Outcomes and Measures: Plasma phospholipid VLSFA levels were measured by thin-layer chromatography followed by gas chromatography. The main outcome was the hazard ratio (HR) of an incident unhealthy aging event associated with serial measures of plasma arachidic acid, behenic acid, and lignoceric acid.

Results: Among the 2680 study participants (976 men [36.4%]), the mean (SD) age was 74.7 (4.8) years old at entry. During a median (interquartile range) of 6.4 (2.9-12.9) years of follow-up, 2484 participants experienced an unhealthy event. Compared with the lowest quintile, levels of behenic acid in the highest quintile of the fatty acid distribution were associated with 15% lower risk of an unhealthy event (HR, 0.85; 95% CI, 0.74-0.97; P for trend = .01) after adjustment for demographic characteristics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of lignoceric acid were similarly associated with 16% lower risk of an unhealthy event (HR, 0.84; 95% CI, 0.73-0.95; P for trend = .001).

Conclusions and Relevance: These findings suggest that higher levels of circulating behenic acid and lignoceric acid are associated with lower risk of unhealthy aging events. These results highlight the need to explore determinants of circulating VLSFAs for potential novel efforts to promote healthy aging.

%B JAMA Netw Open %V 4 %P e2120616 %8 2021 Aug 02 %G eng %N 8 %R 10.1001/jamanetworkopen.2021.20616 %0 Journal Article %J JAMA Netw Open %D 2021 %T Association of Trimethylamine N-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes: The Cardiovascular Health Study. %A Lemaitre, Rozenn N %A Jensen, Paul N %A Wang, Zeneng %A Fretts, Amanda M %A McKnight, Barbara %A Nemet, Ina %A Biggs, Mary L %A Sotoodehnia, Nona %A de Oliveira Otto, Marcia C %A Psaty, Bruce M %A Siscovick, David S %A Hazen, Stanley L %A Mozaffarian, Dariush %X

Importance: Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.

Objective: To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).

Design, Setting, and Participants: This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.

Exposures: Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.

Main Outcomes and Measures: Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.

Results: The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95% CI, 1.04-1.10] for TMAO; 1.07 [95% CI, 1.03-1.10] for carnitine; 1.05 [95% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95% CI, 4.32-8.60] and 2.27 [95% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95% CI, 0.94-1.55] for TMAO; 0.96 [95% CI, 0.74-1.24] for choline; 0.88 [95% CI, 0.67-1.15] for betaine; 1.07 [95% CI, 0.83-1.37] for carnitine; 0.79 [95% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95% CI, 0.83-1.35] for crotonobetaine).

Conclusions and Relevance: Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.

%B JAMA Netw Open %V 4 %P e2122844 %8 2021 Aug 02 %G eng %N 8 %R 10.1001/jamanetworkopen.2021.22844 %0 Journal Article %J J Clin Endocrinol Metab %D 2021 %T Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes. %A Nair, Nandini %A Vittinghoff, Eric %A Pletcher, Mark J %A Oelsner, Elizabeth C %A Allen, Norrina B %A Ndumele, Chiadi E %A West, Nancy A %A Strotmeyer, Elsa S %A Mukamal, Kenneth J %A Siscovick, David S %A Biggs, Mary L %A Laferrère, Blandine %A Moran, Andrew E %A Zhang, Yiyi %K Adolescent %K Adult %K Biomarkers %K Body Mass Index %K Diabetes Mellitus %K Female %K Follow-Up Studies %K Humans %K Male %K Obesity %K Overweight %K Prognosis %K Prospective Studies %K Risk Factors %K United States %K Waist Circumference %K Young Adult %X

CONTEXT: The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied.

OBJECTIVE: To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (≥40 years).

DESIGN: Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis.

SETTING: Population-based cohort studies.

PARTICIPANTS: 30 780 participants (56.1% female, 69.8% non-Hispanic white) without a diagnosis of diabetes by age 40.

INTERVENTIONS: We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life.

MAIN OUTCOME MEASURE(S): Incident diabetes defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of diabetes medications.

RESULTS: During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI ≥ 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49% and 44% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations.

CONCLUSIONS: Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.

%B J Clin Endocrinol Metab %V 106 %P e5011-e5020 %8 2021 11 19 %G eng %N 12 %R 10.1210/clinem/dgab551 %0 Journal Article %J Nat Commun %D 2021 %T Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. %A Harris, William S %A Tintle, Nathan L %A Imamura, Fumiaki %A Qian, Frank %A Korat, Andres V Ardisson %A Marklund, Matti %A Djoussé, Luc %A Bassett, Julie K %A Carmichael, Pierre-Hugues %A Chen, Yun-Yu %A Hirakawa, Yoichiro %A Küpers, Leanne K %A Laguzzi, Federica %A Lankinen, Maria %A Murphy, Rachel A %A Samieri, Cecilia %A Senn, Mackenzie K %A Shi, Peilin %A Virtanen, Jyrki K %A Brouwer, Ingeborg A %A Chien, Kuo-Liong %A Eiriksdottir, Gudny %A Forouhi, Nita G %A Geleijnse, Johanna M %A Giles, Graham G %A Gudnason, Vilmundur %A Helmer, Catherine %A Hodge, Allison %A Jackson, Rebecca %A Khaw, Kay-Tee %A Laakso, Markku %A Lai, Heidi %A Laurin, Danielle %A Leander, Karin %A Lindsay, Joan %A Micha, Renata %A Mursu, Jaako %A Ninomiya, Toshiharu %A Post, Wendy %A Psaty, Bruce M %A Riserus, Ulf %A Robinson, Jennifer G %A Shadyab, Aladdin H %A Snetselaar, Linda %A Sala-Vila, Aleix %A Sun, Yangbo %A Steffen, Lyn M %A Tsai, Michael Y %A Wareham, Nicholas J %A Wood, Alexis C %A Wu, Jason H Y %A Hu, Frank %A Sun, Qi %A Siscovick, David S %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %K Aged %K Aged, 80 and over %K Cause of Death %K Fatty Acids, Omega-3 %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Mortality, Premature %K Prospective Studies %K Protective Factors %K Risk Factors %X

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

%B Nat Commun %V 12 %P 2329 %8 2021 04 22 %G eng %N 1 %R 10.1038/s41467-021-22370-2 %0 Journal Article %J Clin Chem %D 2021 %T Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study. %A Fretts, Amanda M %A Jensen, Paul N %A Hoofnagle, Andrew N %A McKnight, Barbara %A Sitlani, Colleen M %A Siscovick, David S %A King, Irena B %A Psaty, Bruce M %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality.

METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged ≥65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models.

RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95% CI), 1.65-2.17 for Cer-16, 0.79 (95% CI, 0.70-0.88) for Cer-22, 0.74 (95% CI, 0.65-0.84) for Cer-24, 2.51 (95% CI, 2.01-3.14) for SM-16, 0.68 (95% CI, 0.58-0.79) for SM-20, 0.57 (95% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death.

CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

%B Clin Chem %V 67 %P 1650-1659 %8 2021 Nov 26 %G eng %N 12 %R 10.1093/clinchem/hvab182 %0 Journal Article %J Am J Hum Genet %D 2021 %T Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. %A Graff, Mariaelisa %A Justice, Anne E %A Young, Kristin L %A Marouli, Eirini %A Zhang, Xinruo %A Fine, Rebecca S %A Lim, Elise %A Buchanan, Victoria %A Rand, Kristin %A Feitosa, Mary F %A Wojczynski, Mary K %A Yanek, Lisa R %A Shao, Yaming %A Rohde, Rebecca %A Adeyemo, Adebowale A %A Aldrich, Melinda C %A Allison, Matthew A %A Ambrosone, Christine B %A Ambs, Stefan %A Amos, Christopher %A Arnett, Donna K %A Atwood, Larry %A Bandera, Elisa V %A Bartz, Traci %A Becker, Diane M %A Berndt, Sonja I %A Bernstein, Leslie %A Bielak, Lawrence F %A Blot, William J %A Bottinger, Erwin P %A Bowden, Donald W %A Bradfield, Jonathan P %A Brody, Jennifer A %A Broeckel, Ulrich %A Burke, Gregory %A Cade, Brian E %A Cai, Qiuyin %A Caporaso, Neil %A Carlson, Chris %A Carpten, John %A Casey, Graham %A Chanock, Stephen J %A Chen, Guanjie %A Chen, Minhui %A Chen, Yii-der I %A Chen, Wei-Min %A Chesi, Alessandra %A Chiang, Charleston W K %A Chu, Lisa %A Coetzee, Gerry A %A Conti, David V %A Cooper, Richard S %A Cushman, Mary %A Demerath, Ellen %A Deming, Sandra L %A Dimitrov, Latchezar %A Ding, Jingzhong %A Diver, W Ryan %A Duan, Qing %A Evans, Michele K %A Falusi, Adeyinka G %A Faul, Jessica D %A Fornage, Myriam %A Fox, Caroline %A Freedman, Barry I %A Garcia, Melissa %A Gillanders, Elizabeth M %A Goodman, Phyllis %A Gottesman, Omri %A Grant, Struan F A %A Guo, Xiuqing %A Hakonarson, Hakon %A Haritunians, Talin %A Harris, Tamara B %A Harris, Curtis C %A Henderson, Brian E %A Hennis, Anselm %A Hernandez, Dena G %A Hirschhorn, Joel N %A McNeill, Lorna Haughton %A Howard, Timothy D %A Howard, Barbara %A Hsing, Ann W %A Hsu, Yu-Han H %A Hu, Jennifer J %A Huff, Chad D %A Huo, Dezheng %A Ingles, Sue A %A Irvin, Marguerite R %A John, Esther M %A Johnson, Karen C %A Jordan, Joanne M %A Kabagambe, Edmond K %A Kang, Sun J %A Kardia, Sharon L %A Keating, Brendan J %A Kittles, Rick A %A Klein, Eric A %A Kolb, Suzanne %A Kolonel, Laurence N %A Kooperberg, Charles %A Kuller, Lewis %A Kutlar, Abdullah %A Lange, Leslie %A Langefeld, Carl D %A Le Marchand, Loïc %A Leonard, Hampton %A Lettre, Guillaume %A Levin, Albert M %A Li, Yun %A Li, Jin %A Liu, Yongmei %A Liu, Youfang %A Liu, Simin %A Lohman, Kurt %A Lotay, Vaneet %A Lu, Yingchang %A Maixner, William %A Manson, JoAnn E %A McKnight, Barbara %A Meng, Yan %A Monda, Keri L %A Monroe, Kris %A Moore, Jason H %A Mosley, Thomas H %A Mudgal, Poorva %A Murphy, Adam B %A Nadukuru, Rajiv %A Nalls, Mike A %A Nathanson, Katherine L %A Nayak, Uma %A N'diaye, Amidou %A Nemesure, Barbara %A Neslund-Dudas, Christine %A Neuhouser, Marian L %A Nyante, Sarah %A Ochs-Balcom, Heather %A Ogundiran, Temidayo O %A Ogunniyi, Adesola %A Ojengbede, Oladosu %A Okut, Hayrettin %A Olopade, Olufunmilayo I %A Olshan, Andrew %A Padhukasahasram, Badri %A Palmer, Julie %A Palmer, Cameron D %A Palmer, Nicholette D %A Papanicolaou, George %A Patel, Sanjay R %A Pettaway, Curtis A %A Peyser, Patricia A %A Press, Michael F %A Rao, D C %A Rasmussen-Torvik, Laura J %A Redline, Susan %A Reiner, Alex P %A Rhie, Suhn K %A Rodriguez-Gil, Jorge L %A Rotimi, Charles N %A Rotter, Jerome I %A Ruiz-Narvaez, Edward A %A Rybicki, Benjamin A %A Salako, Babatunde %A Sale, Michèle M %A Sanderson, Maureen %A Schadt, Eric %A Schreiner, Pamela J %A Schurmann, Claudia %A Schwartz, Ann G %A Shriner, Daniel A %A Signorello, Lisa B %A Singleton, Andrew B %A Siscovick, David S %A Smith, Jennifer A %A Smith, Shad %A Speliotes, Elizabeth %A Spitz, Margaret %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Sucheston, Lara %A Sun, Yan V %A Tajuddin, Salman M %A Taylor, Herman %A Taylor, Kira %A Tayo, Bamidele O %A Thun, Michael J %A Tucker, Margaret A %A Vaidya, Dhananjay %A Van Den Berg, David J %A Vedantam, Sailaja %A Vitolins, Mara %A Wang, Zhaoming %A Ware, Erin B %A Wassertheil-Smoller, Sylvia %A Weir, David R %A Wiencke, John K %A Williams, Scott M %A Williams, L Keoki %A Wilson, James G %A Witte, John S %A Wrensch, Margaret %A Wu, Xifeng %A Yao, Jie %A Zakai, Neil %A Zanetti, Krista %A Zemel, Babette S %A Zhao, Wei %A Zhao, Jing Hua %A Zheng, Wei %A Zhi, Degui %A Zhou, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Zmuda, Joe %A Zonderman, Alan B %A Psaty, Bruce M %A Borecki, Ingrid B %A Cupples, L Adrienne %A Liu, Ching-Ti %A Haiman, Christopher A %A Loos, Ruth %A Ng, Maggie C Y %A North, Kari E %X

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

%B Am J Hum Genet %V 108 %P 564-582 %8 2021 Apr 01 %G eng %N 4 %R 10.1016/j.ajhg.2021.02.011 %0 Journal Article %J Heart %D 2021 %T Individual non-esterified fatty acids and incident atrial fibrillation late in life. %A Pellegrini, Cara N %A Bůzková, Petra %A Lichtenstein, Alice H %A Matthan, Nirupa R %A Ix, Joachim H %A Siscovick, David S %A Heckbert, Susan R %A Tracy, Russell P %A Mukamal, Kenneth J %A Djoussé, Luc %A Kizer, Jorge R %X

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.

METHODS: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.

RESULTS: The study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.

CONCLUSIONS: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.

%B Heart %8 2021 Jan 22 %G eng %R 10.1136/heartjnl-2020-317929 %0 Journal Article %J J Am Heart Assoc %D 2021 %T Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults. %A Lee, Yujin %A Nemet, Ina %A Wang, Zeneng %A Lai, Heidi T M %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A Fretts, Amanda M %A Sotoodehnia, Nona %A Budoff, Matthew %A DiDonato, Joseph A %A McKnight, Barbara %A Tang, W H Wilson %A Psaty, Bruce M %A Siscovick, David S %A Hazen, Stanley L %A Mozaffarian, Dariush %X

Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time-varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02-1.42; -trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1.07; 95% CI, 0.90-1.27), as well as modified by eGFR (-interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m: HR, 1.56 [95% CI, 1.13-2.14]; -trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m: HR, 1.03 [95% CI, 0.85-1.25]; -trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01-1.56]; -trend=0.009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

%B J Am Heart Assoc %P e020646 %8 2021 Aug 16 %G eng %R 10.1161/JAHA.120.020646 %0 Journal Article %J J Lipid Res %D 2021 %T Plasma Ceramides containing Saturated Fatty Acids are Associated with Risk of Type 2 Diabetes. %A Fretts, Amanda M %A Jensen, Paul N %A Hoofnagle, Andrew N %A McKnight, Barbara %A Howard, Barbara V %A Umans, Jason %A Sitlani, Colleen M %A Siscovick, David S %A King, Irena B %A Djoussé, Luc %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %X

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here we investigated associations of 15 ceramide and sphingomyelin species (i.e., all sphingolipids, measured with coefficient of variation less than 20%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease (CVD) among elderly adults who were followed from 1989-2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dL or non-fasting glucose ≥200 mg/dL; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of ceramide with acylated palmitic acid (Cer-16), stearic acid containing ceramide (Cer-18), arachidic acid containing ceramide (Cer-20), and behenic acid containing ceramide (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each ceramide species were: 1.21 (95% CI 1.09-1.34) for Cer-16, 1.23 (95% CI 1.10-1.37) for Cer-18, 1.14 (95% CI 1.02-1.26) for Cer-20, and 1.18 (95% CI 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

%B J Lipid Res %P 100119 %8 2021 Sep 20 %G eng %R 10.1016/j.jlr.2021.100119 %0 Journal Article %J Heart %D 2021 %T Premature ventricular complexes and development of heart failure in a community-based population. %A Limpitikul, Worawan B %A Dewland, Thomas A %A Vittinghoff, Eric %A Soliman, Elsayed %A Nah, Gregory %A Fang, Christina %A Siscovick, David S %A Psaty, Bruce M %A Sotoodehnia, Nona %A Heckbert, Susan %A Stein, Phyllis K %A Gottdiener, John %A Hu, Xiao %A Hempfling, Ralf %A Marcus, Gregory M %X

OBJECTIVE: A higher premature ventricular complex (PVC) frequency is associated with incident congestive heart failure (CHF) and death. While certain PVC characteristics may contribute to that risk, the current literature stems from patients in medical settings and is therefore prone to referral bias. This study aims to identify PVC characteristics associated with incident CHF in a community-based setting.

METHODS: The Cardiovascular Health Study is a cohort of community-dwelling individuals who underwent prospective evaluation and follow-up. We analysed 24-hour Holter data to assess PVC characteristics and used multivariable logistic and Cox proportional hazards models to identify predictors of a left ventricular ejection fraction (LVEF) decline and incident CHF, respectively.

RESULTS: Of 871 analysed participants, 316 participants exhibited at least 10 PVCs during the 24-hour recording. For participants with PVCs, the average age was 72±5 years, 41% were women and 93% were white. Over a median follow-up of 11 years, 34% developed CHF. After adjusting for demographics, cardiovascular comorbidities, antiarrhythmic drug use and PVC frequency, a greater heterogeneity of the PVC coupling interval was associated with an increased risk of LVEF decline and incident CHF. Of note, neither PVC duration nor coupling interval duration exhibited a statistically significant relationship with either outcome.

CONCLUSIONS: In this first community-based study to identify Holter-based features of PVCs that are associated with LVEF reduction and incident CHF, the fact that coupling interval heterogeneity was an independent risk factor suggests that the mechanism of PVC generation may influence the risk of heart failure.

%B Heart %8 2021 Sep 07 %G eng %R 10.1136/heartjnl-2021-319473 %0 Journal Article %J Cardiology %D 2021 %T Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults. %A Djoussé, Luc %A Biggs, Mary L %A Matthan, Nirupa R %A Ix, Joachim H %A Fitzpatrick, Annette L %A King, Irena %A Lemaitre, Rozenn N %A McKnight, Barbara %A Kizer, Jorge R %A Lichtenstein, Alice H %A Mukamal, Kenneth J %A Siscovick, David S %X

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

RESULTS: The mean age was 77.7 ± 4.4 years, and 38.8% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

%B Cardiology %P 1-8 %8 2021 Feb 25 %G eng %R 10.1159/000513917 %0 Journal Article %J J Am Heart Assoc %D 2021 %T Serum Nonesterified Fatty Acids and Incident Stroke: The CHS. %A Huang, Neil K %A Biggs, Mary L %A Matthan, Nirupa R %A Djoussé, Luc %A Longstreth, W T %A Mukamal, Kenneth J %A Siscovick, David S %A Lichtenstein, Alice H %K 8,11,14-Eicosatrienoic Acid %K Fatty Acids, Nonesterified %K Fatty Acids, Omega-3 %K Hemorrhagic Stroke %K Humans %K Prospective Studies %K Risk Factors %K Stroke %K Trans Fatty Acids %X

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95% CI, 1.02-1.63]), whereas -7-hexadecenoic acid (16:1n-9) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47-0.97]; HR, 0.81 [95% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.

%B J Am Heart Assoc %V 10 %P e022725 %8 2021 11 16 %G eng %N 22 %R 10.1161/JAHA.121.022725 %0 Journal Article %J JAMA Netw Open %D 2022 %T Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults. %A Fretts, Amanda M %A Hazen, Stanley L %A Jensen, Paul %A Budoff, Matthew %A Sitlani, Colleen M %A Wang, Meng %A de Oliveira Otto, Marcia C %A DiDonato, Joseph A %A Lee, Yujin %A Psaty, Bruce M %A Siscovick, David S %A Sotoodehnia, Nona %A Tang, W H Wilson %A Lai, Heidi %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %K Aged %K Betaine %K Cardiovascular Diseases %K Carnitine %K Choline %K Cohort Studies %K Female %K Humans %K Male %K Methylamines %K Prospective Studies %X

Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.

Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.

Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.

Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.

Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.

Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.

Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.

%B JAMA Netw Open %V 5 %P e2213242 %8 2022 05 02 %G eng %N 5 %R 10.1001/jamanetworkopen.2022.13242 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2022 %T Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study. %A Wang, Meng %A Wang, Zeneng %A Lee, Yujin %A Lai, Heidi T M %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A Fretts, Amanda %A Sotoodehnia, Nona %A Budoff, Matthew %A DiDonato, Joseph A %A McKnight, Barbara %A Tang, W H Wilson %A Psaty, Bruce M %A Siscovick, David S %A Hazen, Stanley L %A Mozaffarian, Dariush %K Animals %K Atherosclerosis %K Cardiovascular Diseases %K Carnitine %K Humans %K Meat %K Methylamines %K Risk Factors %X

BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways.

METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways.

RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association.

CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.

%B Arterioscler Thromb Vasc Biol %V 42 %P e273-e288 %8 2022 09 %G eng %N 9 %R 10.1161/ATVBAHA.121.316533 %0 Journal Article %J Heart %D 2022 %T Dysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age. %A Pellegrini, Cara N %A Bůzková, Petra %A Oesterle, Adam %A Heckbert, Susan R %A Tracy, Russell P %A Siscovick, David S %A Mukamal, Kenneth J %A Djoussé, Luc %A Kizer, Jorge R %X

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.

METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.

RESULTS: The study included 1876 participants (age 77.7±4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV·ms, 95% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.

CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.

%B Heart %8 2022 Dec 22 %G eng %R 10.1136/heartjnl-2022-321633 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2022 %T Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and its Subtypes in Older Adults. %A Oesterle, Adam %A Bůzková, Petra %A Pellegrini, Cara %A Hirsch, Calvin %A Tracy, Russell P %A Siscovick, David S %A Djoussé, Luc %A Mukamal, Ken J %A Kizer, Jorge R %X

BACKGROUND: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined.

METHODS: Serum glucose and NEFA were measured during fasting and 2 hours post oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary).

RESULTS: Among 2238 participants (age 78±4) with median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (HR=1.11 per SD [95% CI=1.01-1.23], p=0.040) and post-load (HR=1.14 per SD [1.05-1.24], p=0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR=1.11 [1.003-1.22], p=0.044), but not fasting glucose (HR=1.06 [0.94-1.20], p=0.340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity, and were observed specifically for HFrEF, but not HFpEF.

CONCLUSIONS: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life.

%B J Gerontol A Biol Sci Med Sci %8 2022 Nov 14 %G eng %R 10.1093/gerona/glac229 %0 Journal Article %J Am J Epidemiol %D 2022 %T Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults. %A Shitole, Sanyog G %A Biggs, Mary L %A Ix, Joachim H %A Fretts, Amanda M %A Tracy, Russell P %A Siscovick, David S %A Djoussé, Luc %A Mukamal, Kenneth J %A Kizer, Jorge R %K Aged %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Fasting %K Fatty Acids, Nonesterified %K Female %K Glucose %K Humans %K Insulin %K Insulin Resistance %K Male %K Prospective Studies %X

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

%B Am J Epidemiol %V 191 %P 1235-1247 %8 2022 Jun 27 %G eng %N 7 %R 10.1093/aje/kwac044 %0 Journal Article %J EBioMedicine %D 2022 %T Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study. %A Lemaitre, Rozenn N %A Jensen, Paul N %A Zeigler, Maxwell %A Fretts, Amanda M %A Umans, Jason G %A Howard, Barbara V %A Sitlani, Colleen M %A McKnight, Barbara %A Gharib, Sina A %A King, Irena B %A Siscovick, David S %A Psaty, Bruce M %A Sotoodehnia, Nona %A Totah, Rheem A %K Animals %K Arachidonic Acids %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K Eicosanoids %K Humans %K Ischemic Stroke %K Prospective Studies %X

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

%B EBioMedicine %V 83 %P 104189 %8 2022 Sep %G eng %R 10.1016/j.ebiom.2022.104189 %0 Journal Article %J J Am Heart Assoc %D 2022 %T Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts. %A Lamprea-Montealegre, Julio A %A Arnold, Alice M %A McClelland, Robyn L %A Mukamal, Kenneth J %A Djoussé, Luc %A Biggs, Mary L %A Siscovick, David S %A Tracy, Russell P %A Beisswenger, Paul J %A Psaty, Bruce M %A Ix, Joachim H %A Kizer, Jorge R %K Atherosclerosis %K Cardiovascular Diseases %K Cohort Studies %K Glycation End Products, Advanced %K Humans %K Middle Aged %K Risk Factors %X

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α-dicarbonyl-derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new-onset CVD in 2 population-based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case-cohort sample (n=1631) from the Multi-Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi-Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow-up of 11 years, 439 participants in the Multi-Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl-lysine, 3-deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi-Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α-dicarbonyl-derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle-aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α-dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high-risk older populations.

%B J Am Heart Assoc %V 11 %P e024012 %8 2022 08 02 %G eng %N 15 %R 10.1161/JAHA.121.024012 %0 Journal Article %J Eur J Epidemiol %D 2022 %T Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing. %A Austin, Thomas R %A McHugh, Caitlin P %A Brody, Jennifer A %A Bis, Joshua C %A Sitlani, Colleen M %A Bartz, Traci M %A Biggs, Mary L %A Bansal, Nisha %A Bůzková, Petra %A Carr, Steven A %A deFilippi, Christopher R %A Elkind, Mitchell S V %A Fink, Howard A %A Floyd, James S %A Fohner, Alison E %A Gerszten, Robert E %A Heckbert, Susan R %A Katz, Daniel H %A Kizer, Jorge R %A Lemaitre, Rozenn N %A Longstreth, W T %A McKnight, Barbara %A Mei, Hao %A Mukamal, Kenneth J %A Newman, Anne B %A Ngo, Debby %A Odden, Michelle C %A Vasan, Ramachandran S %A Shojaie, Ali %A Simon, Noah %A Smith, George Davey %A Davies, Neil M %A Siscovick, David S %A Sotoodehnia, Nona %A Tracy, Russell P %A Wiggins, Kerri L %A Zheng, Jie %A Psaty, Bruce M %X

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

%B Eur J Epidemiol %8 2022 Jul 05 %G eng %R 10.1007/s10654-022-00888-z %0 Journal Article %J BMJ %D 2023 %T Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. %A Ong, Kwok Leung %A Marklund, Matti %A Huang, Liping %A Rye, Kerry-Anne %A Hui, Nicholas %A Pan, Xiong-Fei %A Rebholz, Casey M %A Kim, Hyunju %A Steffen, Lyn M %A van Westing, Anniek C %A Geleijnse, Johanna M %A Hoogeveen, Ellen K %A Chen, Yun-Yu %A Chien, Kuo-Liong %A Fretts, Amanda M %A Lemaitre, Rozenn N %A Imamura, Fumiaki %A Forouhi, Nita G %A Wareham, Nicholas J %A Birukov, Anna %A Jäger, Susanne %A Kuxhaus, Olga %A Schulze, Matthias B %A de Mello, Vanessa Derenji %A Tuomilehto, Jaakko %A Uusitupa, Matti %A Lindström, Jaana %A Tintle, Nathan %A Harris, William S %A Yamasaki, Keisuke %A Hirakawa, Yoichiro %A Ninomiya, Toshiharu %A Tanaka, Toshiko %A Ferrucci, Luigi %A Bandinelli, Stefania %A Virtanen, Jyrki K %A Voutilainen, Ari %A Jayasena, Tharusha %A Thalamuthu, Anbupalam %A Poljak, Anne %A Bustamante, Sonia %A Sachdev, Perminder S %A Senn, Mackenzie K %A Rich, Stephen S %A Tsai, Michael Y %A Wood, Alexis C %A Laakso, Markku %A Lankinen, Maria %A Yang, Xiaowei %A Sun, Liang %A Li, Huaixing %A Lin, Xu %A Nowak, Christoph %A Arnlöv, Johan %A Riserus, Ulf %A Lind, Lars %A Le Goff, Mélanie %A Samieri, Cecilia %A Helmer, Catherine %A Qian, Frank %A Micha, Renata %A Tin, Adrienne %A Köttgen, Anna %A de Boer, Ian H %A Siscovick, David S %A Mozaffarian, Dariush %A Wu, Jason HY %K alpha-Linolenic Acid %K Fatty Acids, Omega-3 %K Fatty Acids, Unsaturated %K Humans %K Middle Aged %K Prospective Studies %K Renal Insufficiency, Chronic %K Risk Factors %X

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

%B BMJ %V 380 %P e072909 %8 2023 Jan 18 %G eng %R 10.1136/bmj-2022-072909 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults. %A de Oliveira Otto, Marcia C %A Wu, Jason H Y %A Thacker, Evan L %A Lai, Heidi Tsz Mung %A Lemaitre, Rozenn N %A Padhye, Nikhil %A Song, Xiaoling %A King, Irena B %A Lopez, Oscar %A Siscovick, David S %A Mozaffarian, Dariush %X

BACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.

OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study.

METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.

RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.

CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

%B J Alzheimers Dis %8 2023 Aug 23 %G eng %R 10.3233/JAD-230083 %0 Journal Article %J Metabol Open %D 2023 %T The determinants of fasting and post-load non-esterified fatty acids in older adults: The cardiovascular health study. %A Bene-Alhasan, Yakubu %A Siscovick, David S %A Ix, Joachim H %A Kizer, Jorge R %A Tracy, Russell %A Djoussé, Luc %A Mukamal, Kenneth J %X

AIM: Non-esterified fatty acids (NEFA) are potential targets for prevention of key cardiometabolic diseases of aging, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with fasting and post-load NEFA levels in older adults.

METHODS: We used linear regression to determine the cross-sectional associations of demographic, anthropometric, and lifestyle characteristics and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n = 1924).

RESULTS: Fasting NEFA levels generally demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score was associated with lower levels.

CONCLUSION: Fasting and post-load NEFA have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant study as targets for lowering levels of NEFA in older adults.

%B Metabol Open %V 20 %P 100261 %8 2023 Dec %G eng %R 10.1016/j.metop.2023.100261 %0 Journal Article %J EBioMedicine %D 2023 %T Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events. %A Lidgard, Benjamin %A Bansal, Nisha %A Zelnick, Leila R %A Hoofnagle, Andrew N %A Fretts, Amanda M %A Longstreth, William T %A Shlipak, Michael G %A Siscovick, David S %A Umans, Jason G %A Lemaitre, Rozenn N %X

BACKGROUND: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events.

METHODS: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance.

FINDINGS: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke.

INTERPRETATION: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD.

FUNDING: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

%B EBioMedicine %V 95 %P 104765 %8 2023 Aug 24 %G eng %R 10.1016/j.ebiom.2023.104765 %0 Journal Article %J JAMA Netw Open %D 2023 %T Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study. %A Bockus, Lee B %A Jensen, Paul N %A Fretts, Amanda M %A Hoofnagle, Andrew N %A McKnight, Barbara %A Sitlani, Colleen M %A Siscovick, David S %A King, Irena B %A Psaty, Bruce M %A Sotoodehnia, Nona %A Lemaitre, Rozenn N %K Aged %K Ceramides %K Cohort Studies %K Death, Sudden, Cardiac %K Eicosanoic Acids %K Fatty Acids %K Female %K Humans %K Male %K Sphingolipids %K Sphingomyelins %X

IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).

CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

%B JAMA Netw Open %V 6 %P e2343854 %8 2023 Nov 01 %G eng %N 11 %R 10.1001/jamanetworkopen.2023.43854 %0 Journal Article %J J Am Heart Assoc %D 2023 %T Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis. %A Lemaitre, Rozenn N %A Jensen, Paul N %A Wang, Zeneng %A Fretts, Amanda M %A Sitlani, Colleen M %A Nemet, Ina %A Sotoodehnia, Nona %A de Oliveira Otto, Marcia C %A Zhu, Weifei %A Budoff, Matt %A Longstreth, W T %A Psaty, Bruce M %A Siscovick, David S %A Hazen, Stanley L %A Mozaffarian, Dariush %K Aged %K Atherosclerosis %K Female %K Humans %K Ischemic Stroke %K Methylamines %K Oxides %K Prospective Studies %K Risk Factors %K Stroke %K United States %X

Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60% (CHS) and 53% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

%B J Am Heart Assoc %V 12 %P e8711 %8 2023 Aug 15 %G eng %N 16 %R 10.1161/JAHA.122.029230 %0 Journal Article %J Am J Prev Med %D 2023 %T Time-Varying Food Retail and Incident Disease in the Cardiovascular Health Study. %A Lovasi, Gina S %A Boise, Sarah %A Jogi, Siddharth %A Hurvitz, Philip M %A Rundle, Andrew G %A Diez, Julia %A Hirsch, Jana A %A Fitzpatrick, Annette %A Biggs, Mary L %A Siscovick, David S %X

INTRODUCTION: Natural experiments can strengthen evidence linking neighborhood food retail presence to dietary intake patterns and cardiometabolic health outcomes, yet sample size and follow-up duration are typically not extensive. To complement natural experiment evidence, longitudinal data were used to estimate the impacts of neighborhood food retail presence on incident disease.

METHODS: The Cardiovascular Health Study recruited adults aged 65+ years in 1989-1993. Analyses conducted in 2021-2022 included those in good baseline health, with addresses updated annually through the year of death (restricted to 91% who died during >2 decades of cohort follow-up). Baseline and annually updated presence of 2 combined food retail categories (supermarkets/produce markets and convenience/snack focused) was characterized using establishment-level data for 1-km and 5-km Euclidean buffers. Cox proportional hazards models estimated associations with time to each incident outcome (cardiovascular disease, diabetes), adjusting for individual and area-based confounders.

RESULTS: Among 2,939 participants, 36% with baseline supermarket/produce market presence within 1 km had excess incident cardiovascular disease (hazard ratio=1.12; 95% CI=1.01, 1.24); the association was attenuated and no longer statistically significant after adjustment for sociodemographic characteristics. Adjusted associations were robustly null for time-varying supermarket/produce market or convenience/fast food retail presence across analyses with outcomes of cardiovascular disease or diabetes incidence.

CONCLUSIONS: Food environment changes continue to be studied to provide an evidence base for policy decisions, and null findings in this longitudinal analysis add literature that casts doubt on the sufficiency of strategies targeting food retail presence alone of an elderly cohort for curtailing incident events of clinical importance.

%B Am J Prev Med %8 2023 Mar 05 %G eng %R 10.1016/j.amepre.2023.02.001